CN1145074A - Carbamoylmethylurea derivative - Google Patents
Carbamoylmethylurea derivative Download PDFInfo
- Publication number
- CN1145074A CN1145074A CN95192442A CN95192442A CN1145074A CN 1145074 A CN1145074 A CN 1145074A CN 95192442 A CN95192442 A CN 95192442A CN 95192442 A CN95192442 A CN 95192442A CN 1145074 A CN1145074 A CN 1145074A
- Authority
- CN
- China
- Prior art keywords
- compound
- phenyl
- methyl
- phosphinylidyne
- urea groups
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- NFODSNOCEFVBRY-UHFFFAOYSA-N 2-(carbamoylamino)acetamide Chemical class NC(=O)CNC(N)=O NFODSNOCEFVBRY-UHFFFAOYSA-N 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 201
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 64
- 108010089448 Cholecystokinin B Receptor Proteins 0.000 claims abstract description 28
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 23
- 102000052874 Gastrin receptors Human genes 0.000 claims abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- 230000000694 effects Effects 0.000 claims abstract description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 12
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 6
- -1 carboxyl phenyl Chemical group 0.000 claims description 118
- 229910052760 oxygen Inorganic materials 0.000 claims description 81
- 239000001301 oxygen Substances 0.000 claims description 80
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 69
- 239000000203 mixture Substances 0.000 claims description 47
- 230000003042 antagnostic effect Effects 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 12
- 229940079593 drug Drugs 0.000 claims description 6
- 239000008896 Opium Substances 0.000 claims description 5
- 230000000202 analgesic effect Effects 0.000 claims description 5
- 229960001027 opium Drugs 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- FDATWRLUYRHCJE-UHFFFAOYSA-N diethylamino hydroxybenzoyl hexyl benzoate Chemical compound CCCCCCOC(=O)C1=CC=CC=C1C(=O)C1=CC=C(N(CC)CC)C=C1O FDATWRLUYRHCJE-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 230000000767 anti-ulcer Effects 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 9
- 201000010099 disease Diseases 0.000 abstract description 8
- 102100036016 Gastrin/cholecystokinin type B receptor Human genes 0.000 abstract description 7
- 108010089335 Cholecystokinin A Receptor Proteins 0.000 abstract description 3
- 102100034927 Cholecystokinin receptor type A Human genes 0.000 abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract 1
- 230000001939 inductive effect Effects 0.000 abstract 1
- 125000000547 substituted alkyl group Chemical group 0.000 abstract 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 190
- 238000000034 method Methods 0.000 description 89
- 239000000243 solution Substances 0.000 description 82
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 74
- 238000004458 analytical method Methods 0.000 description 66
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 64
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 63
- 239000012965 benzophenone Substances 0.000 description 63
- 229910052799 carbon Inorganic materials 0.000 description 57
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 57
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 54
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 51
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 42
- 238000006243 chemical reaction Methods 0.000 description 40
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 37
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 37
- 238000003756 stirring Methods 0.000 description 34
- 238000005406 washing Methods 0.000 description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 29
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 28
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 238000003810 ethyl acetate extraction Methods 0.000 description 27
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 27
- 239000000126 substance Substances 0.000 description 25
- 239000002994 raw material Substances 0.000 description 23
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- 239000010410 layer Substances 0.000 description 21
- 239000012044 organic layer Substances 0.000 description 21
- 238000001308 synthesis method Methods 0.000 description 21
- 235000002639 sodium chloride Nutrition 0.000 description 19
- 150000002148 esters Chemical class 0.000 description 18
- 238000012360 testing method Methods 0.000 description 18
- CAVZBWFUMSXZFB-LJWNLINESA-N Amogastrin Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)OC(C)(C)CC)C(N)=O)C1=CC=CC=C1 CAVZBWFUMSXZFB-LJWNLINESA-N 0.000 description 17
- 238000001035 drying Methods 0.000 description 17
- 239000000370 acceptor Substances 0.000 description 16
- 108700042255 amogastrin Proteins 0.000 description 16
- 230000006837 decompression Effects 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 14
- 229910052763 palladium Inorganic materials 0.000 description 14
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 14
- 239000007864 aqueous solution Substances 0.000 description 13
- 229910052938 sodium sulfate Inorganic materials 0.000 description 13
- 235000011152 sodium sulphate Nutrition 0.000 description 13
- 239000000284 extract Substances 0.000 description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 12
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 10
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 10
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 10
- 229940125961 compound 24 Drugs 0.000 description 10
- 238000001953 recrystallisation Methods 0.000 description 10
- 238000007670 refining Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 230000008485 antagonism Effects 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 238000009472 formulation Methods 0.000 description 9
- 150000002576 ketones Chemical class 0.000 description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- 102000005962 receptors Human genes 0.000 description 9
- 108020003175 receptors Proteins 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- 238000012546 transfer Methods 0.000 description 9
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 8
- HCLQARMRCPEALF-DNQXCXABSA-N 3-[[(2r)-2-[(1r)-2-[[1-(1-benzothiophen-2-yl)-2-methylpropan-2-yl]amino]-1-hydroxyethyl]pyrrolidin-1-yl]methyl]benzonitrile Chemical compound C([C@@H]1[C@H](O)CNC(C)(CC=2SC3=CC=CC=C3C=2)C)CCN1CC1=CC=CC(C#N)=C1 HCLQARMRCPEALF-DNQXCXABSA-N 0.000 description 8
- 229940125846 compound 25 Drugs 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- 230000002194 synthesizing effect Effects 0.000 description 8
- CSIFGMFVGDBOQC-UHFFFAOYSA-N 3-iminobutanenitrile Chemical compound CC(=N)CC#N CSIFGMFVGDBOQC-UHFFFAOYSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- 125000003963 dichloro group Chemical group Cl* 0.000 description 7
- 238000012545 processing Methods 0.000 description 7
- KAFZOLYKKCWUBI-HPMAGDRPSA-N (2s)-2-[[(2s)-2-[[(2s)-1-[(2s)-3-amino-2-[[(2s)-2-[[(2s)-2-(3-cyclohexylpropanoylamino)-4-methylpentanoyl]amino]-5-methylhexanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]butanediamide Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CCC(C)C)C(=O)N[C@@H](CN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(N)=O)C(=O)CCC1CCCCC1 KAFZOLYKKCWUBI-HPMAGDRPSA-N 0.000 description 6
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 6
- 239000004471 Glycine Substances 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 150000001413 amino acids Chemical class 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 230000027455 binding Effects 0.000 description 6
- 238000010511 deprotection reaction Methods 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- 150000002367 halogens Chemical class 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 230000028327 secretion Effects 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000011149 active material Substances 0.000 description 5
- 150000001263 acyl chlorides Chemical class 0.000 description 5
- 229940024606 amino acid Drugs 0.000 description 5
- 235000001014 amino acid Nutrition 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 230000001079 digestive effect Effects 0.000 description 5
- 210000004907 gland Anatomy 0.000 description 5
- 239000007937 lozenge Substances 0.000 description 5
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 235000011121 sodium hydroxide Nutrition 0.000 description 5
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 101800001982 Cholecystokinin Proteins 0.000 description 4
- 102100025841 Cholecystokinin Human genes 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 4
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 4
- 150000001350 alkyl halides Chemical class 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 229940107137 cholecystokinin Drugs 0.000 description 4
- 239000003743 cholecystokinin B receptor antagonist Substances 0.000 description 4
- 229940126086 compound 21 Drugs 0.000 description 4
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- 239000012141 concentrate Substances 0.000 description 4
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- 208000000718 duodenal ulcer Diseases 0.000 description 4
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- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 4
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
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- 108090001085 Cholecystokinin Receptors Proteins 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- 208000007107 Stomach Ulcer Diseases 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
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- 201000005917 gastric ulcer Diseases 0.000 description 3
- 125000001072 heteroaryl group Chemical group 0.000 description 3
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
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- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 150000002497 iodine compounds Chemical class 0.000 description 3
- 239000012948 isocyanate Substances 0.000 description 3
- 150000002513 isocyanates Chemical class 0.000 description 3
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 3
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 235000015320 potassium carbonate Nutrition 0.000 description 3
- 235000007715 potassium iodide Nutrition 0.000 description 3
- 229960004839 potassium iodide Drugs 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 3
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- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 description 1
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000005251 gamma ray Effects 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- OHMBHFSEKCCCBW-UHFFFAOYSA-N hexane-2,5-diol Chemical compound CC(O)CCC(C)O OHMBHFSEKCCCBW-UHFFFAOYSA-N 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000006178 methyl benzyl group Chemical group 0.000 description 1
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N methylene hexane Natural products CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 1
- MJVGBKJNTFCUJM-UHFFFAOYSA-N mexenone Chemical compound OC1=CC(OC)=CC=C1C(=O)C1=CC=C(C)C=C1 MJVGBKJNTFCUJM-UHFFFAOYSA-N 0.000 description 1
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical class O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 1
- 229960004715 morphine sulfate Drugs 0.000 description 1
- GRVOTVYEFDAHCL-RTSZDRIGSA-N morphine sulfate pentahydrate Chemical compound O.O.O.O.O.OS(O)(=O)=O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O GRVOTVYEFDAHCL-RTSZDRIGSA-N 0.000 description 1
- FEKRFYZGYUTGRY-UHFFFAOYSA-N n'-ethylmethanediimine Chemical compound CCN=C=N FEKRFYZGYUTGRY-UHFFFAOYSA-N 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- RCSBCWXPGSPJNF-UHFFFAOYSA-N n-[4-[5-[3-chloro-4-(trifluoromethoxy)phenyl]-1,3,4-oxadiazol-2-yl]butyl]-4-(1,8-naphthyridin-2-yl)butanamide Chemical compound C1=C(Cl)C(OC(F)(F)F)=CC=C1C(O1)=NN=C1CCCCNC(=O)CCCC1=CC=C(C=CC=N2)C2=N1 RCSBCWXPGSPJNF-UHFFFAOYSA-N 0.000 description 1
- XZMHJYWMCRQSSI-UHFFFAOYSA-N n-[5-[2-(3-acetylanilino)-1,3-thiazol-4-yl]-4-methyl-1,3-thiazol-2-yl]benzamide Chemical compound CC(=O)C1=CC=CC(NC=2SC=C(N=2)C2=C(N=C(NC(=O)C=3C=CC=CC=3)S2)C)=C1 XZMHJYWMCRQSSI-UHFFFAOYSA-N 0.000 description 1
- MUWDEQLPHWVPPA-GOTSBHOMSA-N n-[6-oxo-6-[(3s,4s)-3-[(4-phenoxyphenyl)sulfonylamino]-4-sulfanylpyrrolidin-1-yl]hexyl]acetamide Chemical compound C1N(C(=O)CCCCCNC(=O)C)C[C@H](S)[C@H]1NS(=O)(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 MUWDEQLPHWVPPA-GOTSBHOMSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- HBEDNENASUYMPO-LJQANCHMSA-N n-hydroxy-4-[[(2r)-3-oxo-2-(thiophen-2-ylmethyl)-2,4-dihydroquinoxalin-1-yl]methyl]benzamide Chemical compound C1=CC(C(=O)NO)=CC=C1CN1C2=CC=CC=C2NC(=O)[C@H]1CC1=CC=CS1 HBEDNENASUYMPO-LJQANCHMSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000005968 oxazolinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 210000001711 oxyntic cell Anatomy 0.000 description 1
- 102000014187 peptide receptors Human genes 0.000 description 1
- 108010011903 peptide receptors Proteins 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- JLXXLCJERIYMQG-UHFFFAOYSA-N phenylcyanamide Chemical compound N#CNC1=CC=CC=C1 JLXXLCJERIYMQG-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- VXBAJLGYBMTJCY-NSCUHMNNSA-N sb1317 Chemical compound N=1C2=CC=NC=1NC(C=1)=CC=CC=1CN(C)C\C=C\CCOC1=CC=CC2=C1 VXBAJLGYBMTJCY-NSCUHMNNSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 238000003375 selectivity assay Methods 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 238000010129 solution processing Methods 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- YRALAIOMGQZKOW-UHFFFAOYSA-N sulfated caerulein Natural products C=1C=CC=CC=1CC(C(N)=O)NC(=O)C(CC(O)=O)NC(=O)C(CCSC)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)CNC(=O)C(C(C)O)NC(=O)C(NC(=O)C(CC(O)=O)NC(=O)C(CCC(N)=O)NC(=O)C1NC(=O)CC1)CC1=CC=C(OS(O)(=O)=O)C=C1 YRALAIOMGQZKOW-UHFFFAOYSA-N 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- JYRWUSXRTGACLY-UHFFFAOYSA-N tert-butyl 4-[[3-(4-methylsulfonylphenyl)-[1,2]oxazolo[4,5-d]pyrimidin-7-yl]oxy]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1OC1=NC=NC2=C1ON=C2C1=CC=C(S(C)(=O)=O)C=C1 JYRWUSXRTGACLY-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Abstract
A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, having a strong affinity for gastrin receptors and/or CCK-B receptors but not for CCK-A receptors and hence being useful for curing diseases related to gastrin receptors and/or CCK-B receptors without inducing side effect related to CCK-A receptors, wherein R1 represents hydrogen or lower alkyl; R2 represents lower alkoxy, lower alkylamino, lower cycloalkyl, optionally substituted phenyl or optionally substituted heterocycle; R3 represents optionally substituted phenyl; and R4 represents optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted alkyl or optionally substituted heterocycle.
Description
Technical field
The present invention relates to can the antagonism tert-Amyloxycarbonyltetragastrin and/or CCK-B and can be specifically and the novel amino formyl methyl urea derivatives of its receptors bind, and contain this derivative and can be used for treating medical composition with the receptor related disease of these tert-Amyloxycarbonyltetragastrin and/or CCK-B.
Background technology
Tert-Amyloxycarbonyltetragastrin and cholecystokinin (CCK) are the physiologically active substances that belongs to so-called tert-Amyloxycarbonyltetragastrin group digestive tube peptide hormone.Though gastrin receptor also is present in whole upper digestive tract, pancreas, liver and the biliary system etc., mainly is present in the fundic gland parietal cell, can regulate gastric acid secretion.On the other hand, cck receptor is known two kinds, a kind of be present in ends such as digestive tube organize slightly in (being called the CCK-A acceptor), another kind is present in the interior maincenter tissue of brain (being called the CCK-B acceptor), the former is related to gastrointestinal motor and pancreatic secretion, and the latter then is related to the adjusting of central action, appetite etc.Therefore, can the antagonism tert-Amyloxycarbonyltetragastrin and/or CCK and can be specifically and the compound of its receptors bind, be expected to can be effectively used to treat in the digestive tube that comprises human various animals and the central nervous system and the receptor related disease of peptide hormone separately.For example, such compound can consider that as antitumour drug perhaps the curative of pancreatitis or cholecystitis is used to alleviate the medicine of gallbladdergallstonecholetithiasis outbreak, appetite activator, the curative of irritable intestine syndrome (irrilable Bowel Syndrome).On the other hand, the result of study about the acceptor in digestive tube and the maincenter tissue shows that these digestive tube peptide hormones also are important (" brain and peptide " metabolism, vol.18, No.10,33-44 (1981) as biologically active substance; J.Hughus, G.Woodruff, D.Horwell, A.McKnight and D.Hill, " Gastrin ", and J.H.Walsh compiles, Rovan Press, and Ltd., NewYork 1933, p.169-186; F.Makovec, Drugs of the Future, 18,919 (1993); The spy opens clear 63-238069 communique; EP 167,919; US 4820834; EP 284,256; US 5004741).
For example, someone thinks the special antagonistic of gastrin receptor be can be used for treating degradation and tert-Amyloxycarbonyltetragastrin diseases associated under stomach ulcer, duodenal ulcer, Zollinger Ellison syndrome, the G hyperplasia of pylorus hole, the tert-Amyloxycarbonyltetragastrin activity, antagonistic availability (metabolism 29/ seven, 1992 in gastric duodenal ulcer treatment special have also been reported to gastrin receptor; R.Eissele, H.Patberg, H.Koop, W.Krack, W.Lorenz, A.T.McKnight and R.Arnold, Gastroente rology, 103,1596 (1992) etc.).
On the other hand, also the someone reports, the CCK-B receptor antagonism can be used for strengthening and continues by class opium medicine (morphine derivatives such as morphine sulfate, Srm-Rhotaard etc.) caused analgesic activity (the Drugs of the Feture of antagonism opioid receptor specifically, 18,919 (1993); Proc.Natl.Acad.Sci.USA, Vol.87, p.71,05 September 1990, Neurobiology).
As what can be used for above-mentioned treatment compound arranged earlier, existing people such as the closed-loop type diaza compounds that gastrin receptor or cck receptor is had antagonistic action (has for example reported, the spy opens the L-365.260 of clear 63-238069 communique record, the YM022 of No. 92/11246 record of WO, and the compound of International Application No. WO 93/14074 and WO 93/14075 record) or closed-loop type compound (people such as Martin J.Drysdale, the CI-988 of J.Med.Chem.35:2573-2581 (1992) record, Drugs of the Future 1993, the RP72540 of 18 (10) records, and J.Pharmacol.Exp.Ther.264, the LY-288513 of 480 (1993) records) etc.Yet,, thereby do not provide clinical application therapeutic agent for ulcer possible, that have the gastrin receptor antagonistic action up to now as yet because great majority are low to the specificitys of each acceptor, also lack concrete pharmacological datum.Therefore, in order to treat more efficiently, can be thereby be necessary to develop with each peptide hormone receptor subtype compound of the preferential and target receptors bind of difference mutually in addition.
Disclosure of the Invention
People such as present inventor, In view of the foregoing, is that purpose is furtherd investigate repeatedly with exploitation to the selectively strong avidity of gastrin receptor and/or CCK-B acceptor but to the very low compound of the avidity of CCK-A acceptor, finally find that some Carbamoylmethylurea derivative can be used for achieving the above object, thereby finished the present invention.
That is, the present invention will provide the compound shown in the general formula (I) or its pharmaceutically acceptable salt:
R in the formula
1Be hydrogen or low alkyl group; R
2Be lower alkoxy, lower alkyl amino, low-grade cycloalkyl, the optional phenyl that replaces arranged or the optional heterocyclic group that replaces is arranged; R
3Be that the optional phenyl that replaces is arranged; R
4Be the optional phenyl that replaces to be arranged, the optional cycloalkyl that replaces is arranged, the optional alkyl that replaces is arranged or the optional heterocyclic group that replaces is arranged.
Although all compounds that meet above-mentioned definition all can be used for reaching the present invention's purpose, be preferably R in the general formula (I)
1Be hydrogen, R
2Be lower alkoxy or lower alkyl amino especially tert.-butoxy, R
3Be that the optional phenyl that replaces especially carboxyl phenyl, R are arranged
4Be that the especially compound of phenyl of the optional phenyl that replaces is arranged.
Implement optimal morphology of the present invention
Below illustrate in greater detail the present invention.
In this specification sheets, " gastrin receptor antagonistic " or " CCK-B receptor antagonist " such term, mean and to suppress gastrin receptor or CCK-B acceptor and native ligand (tert-Amyloxycarbonyltetragastrin or CCK-B) bonded compound separately competitively, can exchange with " tert-Amyloxycarbonyltetragastrin antagonistic " or " CCK-B antagonistic " and use.The compounds of this invention (I) is owing to have strong avidity to gastrin receptor and/or CCK-B acceptor, thereby can also combine with this receptor specifically with the native ligand antagonism of these acceptors, therefore also can be referred to as " gastrin receptor antagonistic " defined above or " CCK-B receptor antagonist ".
Based on above-mentioned same reason, " gastrin receptor antagonistic action " or " CCK-B receptor antagonism " such term also can exchange with " tert-Amyloxycarbonyltetragastrin antagonistic action " or " CCK-B antagonistic action " such term and use.
Term definition in the compound (I) is as follows.
" alkyl " means C
1～C
10The straight or branched alkyl, except that following low alkyl group, can also enumerate octyl group, nonyl, decyl etc.
" low alkyl group " means C
1～C
8The straight or branched alkyl, can enumerate methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, sec.-amyl sec-pentyl secondary amyl, tert-pentyl, n-hexyl, new hexyl, isohexyl, Sec-Hexyl, uncle's hexyl, heptyl and octyl group etc.Be preferably C
1～C
3Alkyl.
" low-grade cycloalkyl " means C
3～C
7, better C
3～C
5Cycloalkyl, can enumerate cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl etc.
" lower alkoxy " means C
1～C
6The alkoxyl group of straight or branched, can enumerate methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, sec-butoxy, tert.-butoxy, n-pentyloxy, isopentyloxy, neopentyl oxygen, secondary pentyloxy, uncle's pentyloxy, positive hexyloxy, new hexyloxy, different hexyloxy, secondary hexyloxy and uncle's hexyloxy etc.Be preferably C
1～C
4Alkoxyl group, especially good is tert.-butoxy.
" lower alkyl amino " means by with amino above-mentioned low alkyl group being replaced the group that forms, for example, can enumerate methylamino-, ethylamino, n-propylamine base, isopropylamino, n-butyl amine base, uncle's fourth amino etc.
" heterocycle " comprises two kinds of heteroaromatic and non-aromatic heterocycles, means independent one or more identical or different heteroatomic five～seven-membered ring of selecting from O, S and N.As the example of such heteroaromatic, can enumerate furyl, thienyl, tetrazyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, Evil pyridine base (oxadinyl) or triazinyl.And, can enumerate pyrrolidyl, thiazolidyl, oxazolidinyl, imidazolidyl, thiazolinyl, oxazolinyl, imidazolinyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, oxadiazole base with alkyl dioxin as non-aromatic heterocyclic example.
As R
2" heterocycle " in the definition, especially good is pyrrolidyl, morpholinyl etc., and as R
4" heterocycle " in the definition particularly contains the heterocycle of N atom, the especially good piperidyl that the amino protecting group protection is randomly arranged.
At R
2In the definition, the substituting group in " have optional replace phenyl " comprises amino, hydroxyl, halogen, low alkyl group, junior alkyl halides etc., can have wherein 1～3 to replace on optional position in ortho position, a position, contraposition.
" halogen " means bromine, chlorine, fluorine, iodine.
At R
2In the definition, the substituting group in " the optional heterocycle that replaces is arranged " comprises amino, hydroxyl, halogen, low alkyl group, junior alkyl halides etc., and can having wherein, 1～3 group replaces.
At R
3In the definition, the substituting group in " have optional replace phenyl " comprise halogen, cyano group, lower alkoxy, low alkyl group, haloalkyl or-R
5-(CH
2)
n-R
6[R
5Be singly-bound ,-O-,-S-or-S (O)-, R
6Be heteroaromatic or-COOR
7(R
7Be hydrogen, low alkyl group, low-grade alkenyl or aralkyl), n is 0～3 integer], NO
2, NH
2, OH, SMe, CONH, OCF
3, CH
2CN, CH
2OH, CH
2OMe, CH
2NH
2Deng, be preferably-COOR
7These groups can replace on any one position in ortho position, a position, contraposition.
" aralkyl " is that aryl replaces on alkyl and the group that forms, means benzyl, styroyl, methyl-benzyl, menaphthyl etc., but good especially be benzyl.
At R
4In the definition, substituting group in " phenyl that optional replacement is arranged ", " the optional alkyl that replaces is arranged ", " the optional heterocycle that replaces is arranged " or " have and choose the cycloalkyl that replaces wantonly " comprises electron-withdrawing group or electron-donating groups such as amino, hydroxyl, halogen, low alkyl group, junior alkyl halides, lower alkoxy, and wherein 1～3 can replace on any one position in ortho position, a position, contraposition.
The group that " haloalkyl " or " junior alkyl halides " means halogen atom on abovementioned alkyl or low alkyl group, better have 1～3 halogen atom to replace, for example-CF
3,-CHF
2,-CH
2F ,-CH
2CCl
3,-CH
2CHClCH
3Deng.
The compounds of this invention (I) can prepare with technical known any method.Below be representational method, but be not limited to these methods.
Method 1
(R in the formula
1, R
2, R
3And R
4As defined above, X is a halogen).
2-substituted aniline derivative shown in the general formula (II) is to carry out under common coupled reaction condition with the reaction that can carry out general formula (III) compound of N-protected as if hope.This coupled reaction can be carried out according to for example following any one method of usual method: 1) use coupling reagent such as dicyclohexyl carbodiimide, 1-(3-dimethylamino-propyl)-direct reaction such as 3-ethyl carbodiimide; 2) amino acid (III) generates acyl chlorides with the thionyl chloride reaction, reacts with ketone compound (II) subsequently; Or 3) reaction composite reactive esters such as amino acid (III) and Vinyl chloroformate are subsequently with ketone compound (II) reaction etc.Then, resultant is used such as common methods such as hydrogen bromide acetic acid solution processing and is carried out suitable deprotection.
Resulting amide compound (IV) and general formula R
2COCH
2Halogenide shown in the X (V) reaction is at suitable alkali for example alkali metal hydroxide (NaOH etc.) or carbonate (K
2CO
3) existence under, in the dimethyl formamide equal solvent, carry out.Resultant of reaction (I) can be further by making substituent R
3Suitably modification is derivatized to other compound (I) that also can be used for reaching the object of the invention.End product can be with refining means commonly used in this technical field respectively, for example with organic solvent extractions such as ethyl acetate, drying, concentrate, chromatography is separated, with the appropriate solvent crystallization etc., make with extra care.
Method 2
(R in the formula
1, R
2, R
3, R
4With X with above definition).
The initial substance aminocompound (VI) of method 2 be by such as allow the ketone compound shown in the above-mentioned general formula (II) with have a suitable side chain R
1N-protected amino acid derivative reaction, deprotection obtains then.
The reaction of ketone compound (II) and N-protected amino acid derivative and deprotection are the same with above-mentioned method 1, also are to carry out under common coupled reaction and deprotection condition.
The reaction of isocyanate derivates shown in aminocompound (VI) and the general formula (VII) is at room temperature carried out both mixing in appropriate solvent.
Then, the same with method 1, make amide compound (IV) and halogenide (V) reaction obtain general formula (I) compound, if wish also can carry out suitable modification, be derivatized to other compound of the present invention (I).
In addition, can also be prepared with the method shown in the following reaction formula.
Method 3
(R in the formula
1, R
2, R
3, R
4With X with above-mentioned definition, L represents low alkyl group).
Starting raw material (VIII) can obtain by the amide compound deprotection that adjacent Iodoaniline and the coupling of Cbz glycine are obtained.Compound (VIII) and isocyanate derivates (VII), react in appropriate solvent in the presence of alkali such as triethylamine in room temperature.Then, Same Way 1 is the same, allows acid amides (IX) and halogenide (V) react, synthetic iodine compound (X).Iodine compound (X) reacts with six alkyl, two tin in the presence of trans-benzyl chloride two (triphenyl phosphine) palladium and tetraethylammonium chloride catalyzer, obtains Alkyzin compound (XI).This tin compound (XI) reacts in the presence of dichloro diacetonitrile palladium catalyst with acyl chlorides, obtains compound (I).
Method 4
(R in the formula
1, R
2, R
3, R
4, L and X be with above-mentioned definition, Cbz represents the benzyloxy phosphinylidyne).
Iodine compound (VIII ') with method 3 the same and six alkyl, two tin reactions, obtain Alkyzin compound (XII).Then, allow compound (XII) and acyl chloride reaction, obtain ketone compound (XIII), obtain amine compound (XIII ') behind the deprotection.Amine compound (XIII ') mixes with synthetic isocyanic ester on the spot, obtains carbamide compound (XV), then with method 1 the same with halogenide (V) reaction, obtain compound (I).
Above-mentioned each method just is applicable to the numerical example in the method for The compounds of this invention (I) preparation, also known any means in suitable initial substance and this technical field respectively can be made up and prepare The compounds of this invention (I), the compound (I) for preparing with such method also belongs to the scope of the invention.
The compounds of this invention (I) can with commonly used mineral acid or organic acid, perhaps mineral alkali or organic bases generate salt.The salt of compound (I) comprises, for example with the salt of basic metal such as sodium, potassium or alkaline-earth metal such as calcium, magnesium; For example with ammonium, Trimethylamine 99, triethylamine, pyridine, picoline, dicyclohexyl amine, N, the salt of N '-organic basess such as dibenzyl-ethylenediamin; For example with organic acid salt such as acetate, toxilic acid, tartrate, methylsulfonic acid, Phenylsulfonic acid, formic acid, toluenesulphonic acids, trifluoroacetic acids; For example with the salt of mineral acids such as hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid; For example with amino acid whose salt such as arginine, aspartic acid, L-glutamic acid.Salt is the inorganic salts of using always preferably.
The antiacid secretion of Carbamoylmethylurea derivative of the present invention (I) is in experiment made on the living (Schild method; With reference to experimental example 1) in be confirmed.In addition, the gastrin receptor antagonistic action and the CCK-B receptor antagonism of all cpds also carried out experiment made on the living, the result shows that Carbamoylmethylurea derivative (I) has these two kinds effects (with reference to experimental example 2).It is evident that from these experimental results Carbamoylmethylurea derivative (I) has antiacid secretion, and sufficient function separation property is arranged between the CCK-A acceptor, is excellent gastrin receptor and/or CCK-B receptor antagonist.
Like this, the Carbamoylmethylurea derivative of The compounds of this invention and salt pair gastrin receptor thereof and/or CCK-B acceptor have strong affinity, and stimulate the acid secretion that causes that the inhibitor effect is also arranged to Peptavlon in the live test.Therefore, this derivative and salt thereof can not bring out the side effect receptor related with CCK-A, can be used as because of disease that the physiological function obstacle that is subjected to gastrin receptor control brings out, especially stomach ulcer, duodenal ulcer, gastritis, adverse current esophagitis, the syndromic curative of Zuo Linge-Ai Lisen (Zollinger-Ellison).In addition, owing to it is believed that the analgesic activity (bringing out property of class opium analgesic activity) that class opium class medicine is produced enhancing or continuous action are arranged also, thereby also be expected to produce better effect with this class analgesic agent and time spent.
Therefore, the invention provides the medical composition that contains compound shown in the general formula (I) and pharmaceutically acceptable carrier, vehicle etc.
In more detail, the invention provides a kind of medical composition, wherein contain the compound (I) and the pharmaceutically acceptable carrier for the treatment of significant quantity, it can not bring out the side effect receptor related with CCK-A, and can be used as because of disease that the physiological function obstacle that is subjected to gastrin receptor control brings out, the curative of stomach ulcer, duodenal ulcer, gastritis, adverse current esophagitis, Zollinger Ellison syndrome especially.
And, the present invention also provides a kind of medical composition, wherein contain the compound (I) and the pharmaceutically acceptable carrier for the treatment of significant quantity, it can not bring out the side effect receptor related with CCK-A, and can treat the central nervous system disorder that brings out because of the physiological function obstacle that is subjected to the control of CCK-B acceptor effectively, for example can be used as the treatment of diseases medicine or the minor tranquilizer (antianxiety agent) that bring out because of the appetite stimulator system disorders.In addition, The compounds of this invention (I) has analgesic activity enhancing or the lasting effect that class opium class medicine is produced owing to it is believed that, thereby with these analgesic agents and with also being expected to produce better effect.
The compounds of this invention (I) can use separately, also can and use with other medicines.And be mixed and made into a kind of medical composition or undertaken by successive administration with known method and pharmaceutically acceptable any one above activeconstituents on the treatment available techniques.
Under the situation that The compounds of this invention (I) is used for the treatment of, but these derivative oral administrations or non-oral administration.Under peroral administration situation, The compounds of this invention can be made into common preparation, as solid dosages such as lozenge, powder, granule, capsules; Aqua, oil-suspending agent or liquid dosage forms such as syrup or elixir, wherein any formulation all can be used.Under para-oral situation, The compounds of this invention can water base or oil-based suspension injection form use.In preparation during these formulations, both can use any in vehicle commonly used, binding agent, lubricant, water-based solvent, oil-based solvent, emulsifying agent, the suspension agent etc., also can contain other additive such as sanitas, stablizer etc.
The dosage of The compounds of this invention is different because of medication, patient's age, body weight, situation and kinds of Diseases, usually under peroral administration situation, be grownup's every day about 5～500mg, be preferably about 10～200mg, be more preferably about 20～100mg, can be once or administration at twice.Under para-oral situation, grownup's every day about 1～20mg, be preferably about 2～10mg, can be once or administration at twice.
Below describe the present invention in detail with embodiment, but these only illustrate, and do not limit the scope of the present invention.
Embodiment
Preparation example 12-(benzyloxy phosphinylidyne glycyl amino) benzophenone 2a
1) triethylamine (26ml) is added drop-wise to 2-Uvinul A Plus (12g under ice-cold, 60.8mmol), N-benzyloxy phosphinylidyne (Cbz) glycine (12.73g, 60.8mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (12.25g, 63.9mmol) and I-hydroxybenzotriazole (1.07g is in tetrahydrofuran (THF) 7.9mmol) (250ml) mixture.Mixture is at one night of stirring at room.In the impouring water, resulting mixture ethyl acetate extraction.The extraction liquid underpressure distillation.Residue 2-propyl alcohol recrystallization.Yield 65%.mp115-117℃。IR ν
Max(KBr): 3306,1693,1637,1538,1534,1521cm
-1.NMR (CDCl
3) δ: 4.07 (2H, d, J=5.8Hz), 5.17 (2H, s), 5.52 (1H, br, s), 7.1-7.69 (9H, m), 8.63 (1H, d, J=8.6Hz), 11.36 (1H, br, s). ultimate analysis (C
23H
20N
2O
4) calculated value: C, 71.12; H, 5.19; N, 7.21 measured values: C, 71.35; H, 5.36; N, 7.28.
2) under-4～5 ℃ of stirrings, to N-benzyloxy phosphinylidyne glycine (12.6g, drip in 6-methyl phosphonic triamide 60mmol) (70ml) and acetonitrile (20ml) solution thionyl chloride (4ml, 55mmol), then-5 ℃ of restir 10 minutes.In reaction solution, divide add for 5 times the 2-Uvinul A Plus (9.86g, 50mmol), then stirring at room 3 hours.Reaction solution with in the saturated sodium bicarbonate aqueous solution and after, use ethyl acetate extraction.Organic layer washing, dry (sal epsom) back concentrating under reduced pressure.Resulting crude product obtains title compound 2a (18.89g, 97.3%) with methylene dichloride and hexane recrystallization.
Preparation example 2 (-)-and (+)-2-(benzyloxy phosphinylidyne alanyl amino) benzophenone 2b, 2c
Carry out the processing same with N-benzyloxy phosphinylidyne-L-L-Ala, obtain (-)-the 2b isomer with above-mentioned preparation example 1.Yield 74.0%.Mp95 ℃ of .[α]
D 24-16.7 (c1.046, CHCl
3) .IR ν
Max(KBr): 3290,1728,1697,1585,1512cm
-1.NMR (CDCl
3) δ: 1.52 (3H, d, J=7.0Hz), 4.45 (1H, m), 5.14 (2H, s), 5.45 (1H, d, J=5.0Hz), 7.12 (1H, dt, J=1.8,8.0Hz), 7.2-7.7 (13H, m), 8.65 (1H, d, J=10.0Hz). ultimate analysis (C
24H
22N
2O
4) calculated value: C, 71.63; H, 5.51; N, 6.96 measured values: C, 71.64; H, 5.49; N, 6.99.
(+)-isomer (compound 2c) is as initial substance, also with the same synthetic of (-)-isomer (compound 2b) with N-benzyloxy phosphinylidyne-d-L-Ala.
[α]
D 23＋13.6(c1.01，CHCl
3)。
Preparation example 3 2-(glycyl amino) benzophenone hydrobromate 3a
(8.06mmol) mixture with 30% Hydrogen bromide acetic acid solution stirred 1 hour the N-benzyloxy phosphinylidyne derivative that preparation example 1 obtains for 2a, 3.13g.Add excessive ether, the precipitation that is generated is leached.Wash after drying with ether, obtain hydrobromate (compound 3a) 2.50g (92%).NMR(CDCl
3)δ：3.42(2H，br.s)，4.11(2H，br.s)，6，95(1H，t，J＝7.8Hz)，7.3-8.22(9H，m)，10.80(1H，br.s)。
Preparation example 4 (-)-and (+)-2-(alanyl amino) benzophenone hydrobromate 3b and 3c
As initial substance, carry out the processing the same with the compound 2b of preparation example 2 preparation and 2c, obtain target compound 3b and 3c with above-mentioned preparation example 3.
Preparation example 5 2-(N '-(tolyl) urea groups methyl carbon acylamino) benzophenone 4a
(0.846g, dimethyl formamide 6.35mmol) (3ml) solution add the salt 3a of preparation example 3 preparation to, and (1.937g is in dimethyl formamide 5.78mmol) (8ml) solution for isocyanate-m-tolyl.Add triethylamine (32ml) at 0 ℃.Mixture stirred 30 minutes at 0 ℃, then at one night of stirring at room.Add water, add 10% hydrochloric acid then.The mixture ethyl acetate extraction.Steam solvent under extract washing, the decompression of dry (sodium sulfate) back.Residue acetonitrile recrystallization obtains target compound 4a (1.39g; Yield 62%).IR ν
Max(KBr): 3310,1684,1639,1590,1523cm
-1.NMR (CDCl
3) δ: 2.21 (3H, s) .4.07 (2H, d, J=5.4Hz), 5.93 (1H, t, J=5.7Hz), 6.83 (1H, m), 7.07-7.65 (13H, m), 8.56 (1H, d, J=8.8Hz), 11.20 (1H, s). ultimate analysis (C
23H
21N
3O
3) calculated value: C, 71.30; H, 5.46; N, 10.85 measured values: C, 71.45; H, 5.54; N, 10.90.
Preparation example 6 (+)-and (-)-2-(1-(N '-(tolyl) urea groups) the ethylamino formyl) benzophenone 4b, 4c
As initial substance, carry out the processing the same with the compound 3b of preparation example 4 preparation and 3c, obtain the compound 4b and the 4c of correspondence with preparation example 5.Compound (4b) yield 75.0%, Mp:160 ℃ [α]
D 23+ 18.8 (c1.075, CHCl
3) .IR ν
Max(nujol): 3298,1683,1651,1636,1582,1552cm
-1.NMR (CDCl
3) δ: 1.45 (3H, d, J=7.0Hz), 2.19 (3H, s), 4.61 (1 H, qui, J=7.0Hz), 5.95 (1H, br.s), 6.79 (1H, br.s), 7.0-7.7 (12H, m), 8.55 (1H, d, J=8.6Hz), 11.32 (1H, s). ultimate analysis (C
24H
23N
3O
3) calculated value: C, 71.80; H, 5.77; N, 10.49 measured values: C, 71.63; H, 5.88; N, 10.55.Compound (4c) [α]
D 23-21.6 (c1.012, CHCl
3)
R
8=a:-COOCH
2Ph, b:-COOCH
2CH=CH
2, c:-CH
2COOCH
2CH=CH
2,
D:-OCH
2COOCH
2CH=CH
2, e:-SCH
2COOCH
2CH=CH
2,
M:-CH
2COOMe, t:-CF
3U:m-Cl, v:m-Br, w:m-CN, x:m-OCH
3, y:p-Cl, z:p-Me, aa:H preparation example 7 2-(N '-((benzyloxy phosphinylidyne) phenyl) urea groups methylamino formyl) benzophenone 6a
With the compound 3a and corresponding isocyanic ester of preparation example 3 preparation, according to the same being prepared of method of preparation example 5.Mp：157-159℃。IR ν
Max(KBr): 3360,1720,1680,1635,1584,1560,1520cm
-1.NMR (DMSO-d
6) δ: 3.74 (2H, d, J=5.2Hz), 5.33 (2H, s), 6.51 (1H, br.s), 7.20-7.70 (16H, m), 7.88 (1H, d, J=8.8Hz), 8.06 (1H, br.s), 9.13 (1H, s), 10.53 (1H, s). ultimate analysis (C
30H
25N
3O
5) calculated value: C, 71.00; H, 4.97; N, 8.28 measured values: C, 71.15; H, 5.06; N, 8.30.
Preparation example 8 2-(N '-(-(2-propenyl oxygen phosphinylidyne) phenyl) urea groups methylamino formyl) benzophenone 6b
The same with preparation example 7, synthetic from compound 3a and corresponding isocyanic ester.Mp：68-71℃。IR ν
Max(KBr): 3350,1718,1692,1659,1595,1580,1557,1520cm
-1NMR (CDCl
3) δ: 4.12 (2H, d, J=5.6Hz), 4.77 (2H, d, J=5.6Hz), 5.20-5.43 (2H, m), and 5.88-6.10 (2H, m), 7.04-7.18 (3H, m), 7.36-7.70 (10H, m), 7,90 (1H, br.s), 8.54 (1H, d, J=8.6Hz). ultimate analysis (C
26H
23N
3O
5) calculated value: C, 68.26; H, 5.07; N, 9.19 measured values: C, 68.30; H, 5.19; N, 9.16.
Preparation example 9 2-(N '-(-(2-propenyl oxygen phosphinylidyne methyl) phenyl) urea groups methylamino formyl) benzophenone 6c
The same with preparation example 7, synthetic from compound 3a and corresponding isocyanic ester.Mp：125-127℃。IR ν
Max(KBr): 3330,1740,1682,1639,1600,1560,1520cm
-1.NMR (CDCl
3) δ: 3.55 (2H, s), 4.08 (2H, d, J=5.8Hz), 4.56 (2H, d, J=5.8Hz), and 5.13-5.32 (2H, m), 6.91-5.98 (2H, m), 6.91-6.99 (1H, m), 7.05-7.32 (6H, m), 7.38-7.70 (7H, m), 8.57 (1H, d, J=8.6Hz). ultimate analysis (C
27H
25N
3O
5) calculated value: C, 68.78; H, 5.34; N, 8.91 measured values: C, 68.89; H, 5.46; N, 8.88.
Preparation example 10 2-(N '-(-(2-propenyl oxygen phosphinylidyne methoxyl group) phenyl) urea groups methylamino formyl) benzophenone 6d
The same with preparation example 7, synthetic from compound 3a and corresponding isocyanic ester.Mp：147-149℃。IR ν
Max(KBr): 3330,1748,1680,1653,1638,1605,1563,1530,1500cm
-1.NMR (CDCl
3) δ: 4.11 (2H, d, J=5.8Hz), 4.58 (2H, s), 5.18-5.37 (2H, m), 5.70-5.99 (2H, m), 6.60 (1H, dd, J=7.6,2.6Hz), 6.90 (1H, d, J=9.0Hz), 7.05-7.18 (4H, m), and 7.40-7.71 (7H, m), 8.59 (1H, d, J=10.0Hz), 11.28 (1H, s). ultimate analysis (C
27H
25N
3O
6) calculated value: C, 66.52; H, 5.17; N, 8.62 measured values: C, 66.54; H, 5.25; N, 8.66.
Preparation example 11 2-(N '-(-(2-propenyl oxygen phosphinylidyne methylthio group) phenyl) urea groups methylamino formyl) benzophenone 6e
The same with preparation example 7, synthetic from compound 3a and corresponding isocyanic ester.IR ν
Max(CHCl
3): 3350,1733,1682,1640,1584,1521cm
-1.NMR (CDCl
3) δ: 3.60 (2H, s), 4.09 (2H, d, J=5.6Hz), 4.47-4.62 (2H, m), 5.10-5.31 (2H, m), 5.70-5.93 (1H, m), 6.00-6.15 (1H, br.s), 6.92-7.20 (4H, m), 7.32-7.71 (9H, m), 8.56 (1H, d, J=8.6Hz). ultimate analysis (C
27H
25N
3O
5S) calculated value: C, 63.94; H, 5.05; N, 8.28; S, 6.32 measured values: C, 63.96; H, 5.18; N, 8.24; S, 6.29.
Preparation example 12 2-(N '-(-(2-(trityl) tetrazolium-5-yl) phenyl) urea groups methylamino formyl) benzophenone 6f
From the 3-anthranilo nitrile according to disclosed method synthetic 3-amino EPO 508769 A1-(1H-(trityl) tetrazolium-5-yl) benzene (567mg, 3.52mmol) synthesizing isocyanate on the spot, synthetic with 3a then by method described in the preparation example 5.It is Powdered that product is.IR ν
Max(KBr): 3375,1695,1660,1640,1595,1580,1560,1513cm
-1NMR (CDCl
3) δ: 4.06 (2H, d, J=5.8Hz), 5.91 (1H, br.s), 6.95-7.80 (28H, m), 7.91 (1H, s), 8.50 (1H, d, 10.0Hz). ultimate analysis (C
42H
33N
7O
30.5H
2O) calculated value: C, 72.82; H, 4.95; N, 14.15 measured values: C, 72.92; H, 5.17; N, 13.16.
Preparation example 13 2-(N '-(-(2-(trityl) tetrazolium-5-ylmethoxy) phenyl) urea groups methyl carbon acylamino) benzophenone 6g
The same with preparation example 7, the isocyanic ester that obtains on the spot from compound 3a with from 3-amino-(1H-(three benzene toluenes) tetrazyl methoxyl group) benzene and triphosgene is synthetic.IR ν
Max(KBr): 3380,1690,1660,1639,1600,1580,1553,1520cm
-1.NMR (CDCl
3) δ: 4.04 (2H, d, J=5.8Hz), 5.24 (2H, s), 5.93 (1H, t, J=5.8Hz), 6.61-6.69 (1H, m), 6.88-7.65 (24H, m), 8.59 (1H, d, J=8.8Hz), 11.28 (1H, s). ultimate analysis (C
43H
35N
7O
40.5CH
3C
6H
5) calculated value: C, 73.50; H, 5.17; N, 12.90 measured values: C, 73.30; H, 5.37; N, 12.90.
Preparation example 14 2-(N '-(-(trifluoromethyl) phenyl) urea groups methyl carbon acylamino) benzophenone 6t
With the compound 3a of preparation example 3 preparation and-(trifluoromethyl) phenyl isocyanate, according to the method preparation of preparation example 5.Yield 74%, Mp:177-178 ℃.NMR(CDCl
3)δ：4.15(2H，s)，5.97-6.32(1H，br.s)，7.30-7.73(13H，m)，8.53(1H，d，J＝8.6Hz)，11.27(1H，s)
Preparation example 15 2-(N '-(chloro-phenyl-) urea groups methyl carbon acylamino) benzophenone 6u
(756mg, tetrahydrofuran (THF) 4.92mmol) (8ml) solution add the salt 3a of preparation example 3 preparation to, and (1.341g is in tetrahydrofuran (THF) 4mmol) (50ml) solution the m-chloro phenyl isocyanate.(1.67 μ l, 12mmol), mixture stirred 30 minutes at 0 ℃, then in stirred overnight at room temperature to add triethylamine at 0 ℃.Add water, add 10% hydrochloric acid then, the mixture ethyl acetate extraction.Behind extract washing, dry (sodium sulfate), decompression steams solvent.Residue obtains target compound 6u (1.43g, yield 73%) with methylene dichloride/diisopropanol recrystallization.IRν
max(KBr)：1691，1639，1593，1556，1523cm
-1.NMR(CDCl
3)δ：4.08(2H，s)，6.90-7.33(5H，m)，7.40-7.73(8H，m)，8.54(1H，d，J＝8.2Hz)，11.21(1H，s).
Preparation example 16 2-(N '-(bromophenyl) urea groups methyl carbon acylamino) benzophenone 6v
To from m-bromoaniline (846mg, 4.92mmol), triphosgene (551mg, 1.72mmol) and triethylamine (960 μ l, 6.9mmol) tetrahydrofuran (THF) (50ml) solution with in the bromine isocyanate solution between the preparation of the described method of EP-508796-A1, at ice-cooled compound 3a (1.341g, tetrahydrofuran (THF) 4mmol) (10ml) solution that adds preparation example 3 preparations down.(558 μ l 4mmol), carry out the processing the same with the method for preparation example 5, make compound 6v (1.45g, yield 68%) to add triethylamine then.IRν
max(KBr)：1682，1638，1590，1554，1523cm
-1NMR(CDCl
3＋CD
3OD)δ：4.10(2H，d，J＝5.7Hz)，6.11(1H，br.s)，6.99-7.30(5H，m)，7.41-7.70(8H，m)，8.54(1H，d，J＝8.4Hz)，11.23(1H，s)
Preparation example 17 2-(N '-(m-aminophenyl base) urea groups methyl carbon acylamino) benzophenone 6w
To from a cyano-aniline (581mg, 4.92mmol), triphosgene (551mg, 1.72mmol) and triethylamine (960 μ l, 6.9mmol) tetrahydrofuran (THF) (50ml) solution with in the bromine isocyanate solution between the method preparation of EP-508796-A1 record, at ice-cooled compound 3a (1.341g, tetrahydrofuran (THF) 4mmol) (10ml) solution that adds preparation example 3 preparations down.(558 μ l 4mmol), carry out the processing the same with the method for preparation example 5, make compound 6w (1.4g, yield 88%) to add triethylamine then.IRν
max(KBr)：2230，1686，1638，1603，1589，1558，1522cm
-1.NMR(CDCl
3＋CD
3OD)δ：4.09(2H，d，J＝5.7Hz，7.09-7.72(13H，m)，8.53(1H，d，J＝8.7Hz)，11.22(1H，s).
Preparation example 18 2-(N '-(m-methoxyphenyl) urea groups methyl carbon acylamino) benzophenone 6x
(734mg, tetrahydrofuran (THF) 4.92mmol) (8ml) solution add the salt 3a of preparation example 3 preparation to, and (1.341g is in tetrahydrofuran (THF) 4mmol) (50ml) solution the m-methoxyphenyl isocyanic ester.(558 μ l, 4mmol), mixture is 0 ℃ of stirring 30 minutes, then in stirred overnight at room temperature to add triethylamine at 0 ℃.Add water, add 10% hydrochloric acid then, the mixture ethyl acetate extraction.Behind extract washing, dry (sodium sulfate), steam solvent under the decompression.Residue makes target compound 6x (1.29g, 80%) with methylene dichloride/diisopropyl ether recrystallization.IRν
max(KBr)：1693，1640，1619，1606，1591，1560，1515cm
-1.NMR(CDCl
3)δ：3.68(3H，s)，4.08(2H，d，J＝2.9Hz)，5.99(1H，d，J＝5.8Hz)，6.56(1H，dd，J＝8.0，1.8Hz)，6.79(1H，dd，J＝7.4，1.0Hz)，7.00-7.16(3H，m)，7.37-7.69(8H，m)，8.55(1H，d，J＝7.8Hz)，11.27(1H，s).
Preparation example 19 2-(N '-(rubigan) urea groups methyl carbon acylamino) benzophenone 6y
(756mg, tetrahydrofuran (THF) 4.92mmol) (8ml) solution add the salt 3a of preparation example 3 preparation to, and (1.341g is in tetrahydrofuran (THF) 4mmol) (50ml) solution the rubigan isocyanic ester.(558 μ l, 4mmol), mixture stirred 30 minutes at 0 ℃, then in stirred overnight at room temperature to add triethylamine at 0 ℃.Add water, add 10% hydrochloric acid then, the mixture ethyl acetate extraction.Behind extract washing, dry (sodium sulfate), steam solvent under the decompression.Residue makes target compound 6y (1.48g, 76%) with methylene dichloride/diisopropyl ether recrystallization.IR ν
Max(KBr): 1686,1636,1591,1558,1522cm
-1.NMR (CDCl
3+ CD
3OD) δ: 4.06 (2H, d, J=5.7Hz), 6.31 (1H, t, J=6.0Hz), 7.11-7.70 (13H, m), 8.52 (1H, d, J=7.5Hz). preparation example 20 2-(N '-(p-methylphenyl) urea groups methyl carbon acylamino) benzophenone 6z
(655mg, tetrahydrofuran (THF) 4.92mmol) (8ml) solution add the salt 3a of preparation example 3 preparation to, and (1.34lg is in tetrahydrofuran (THF) 4mmol) (50ml) solution to toluene diisocyanate.(558 μ l, 4mmol), mixture is 0 ℃ of stirring 30 minutes, then in stirred overnight at room temperature to add triethylamine at 0 ℃.Add water, add 10% hydrochloric acid then, the mixture ethyl acetate extraction.Behind extract washing, dry (sodium sulfate), steam solvent under the decompression.Residue makes target compound 6z (1.311g, 85%) with methylene dichloride/diisopropyl ether recrystallization.IRν
max(KBr)：1685，1639，1604，1593，1555，1519cm
-1.NMR(CDCl
3)δ：2.27(3H，s)，4.07(2H，d，J＝6.0Hz)，5.93(1H，br.s)，7.0-7.29(6H，m)，7.43-7.68(7H，m)，8.56(1H，d，J＝8.4Hz)，11.22(1H，s).
Preparation example 21 2-(N '-phenylurea ylmethyl carbon acylamino) benzophenone 6aa
(440mg, tetrahydrofuran (THF) 3.69mmol) (8ml) solution add the salt 3a of preparation example 3 preparation to, and (1.005g is in tetrahydrofuran (THF) 3mmol) (50ml) solution the benzene isocyanic ester.(911mg, 9mmol), mixture is 0 ℃ of stirring 30 minutes, then in stirred overnight at room temperature to add triethylamine at 0 ℃.Add water, add 10% hydrochloric acid then, the mixture ethyl acetate extraction.Behind extract washing, dry (sodium sulfate), steam solvent under the decompression.Residue makes target compound 6aa (750mg, 67%) with methylene dichloride/diisopropyl ether recrystallization.IRν
max(KBr)：1685，1638，1595，1583，1556，1523cm
-1.NMR(CDCl
3＋CD
3OD)δ：4.07(2H，s)，6.93-7.70(14H，m)，8.54(1H，d，J＝8.4Hz)，11.22(1H，s).
R
8＝a：-CH
3?b：-CF
3?c：-COOCH
2CH＝CH
2
Preparation example 22 cyclohexyl-(2-(benzyloxy carbon acylamino methylamino formyl) phenyl) ketone 12
With document (M.S.Chambers, S.C.Hobbs, S.R.Fletcher, V.G.Matassa, P.J.Mitchell, A.P.Watt, R.Baker, S.B.Freedman, S.Patel and A.J.Smith, Bioorg.Med.Chem.Lett., 3,1919 (1993)) Ji Zai compound cyclohexyl-(2-aminophenyl) ketone 11 is according to the method synthesising title compound of preparation example 1.Mp:152-155 ℃ of IR ν
Max(KBr): 3324,1669,1694,1641,1602,1582,1517cm
-1.NMR (CDCl
3) δ: 1.13-1.61 (5H, m), 1.69-1.94 (5H, m), 3.31 (1H, m), 4.09 (1H, d, J=5.6Hz), 5.20 (2H, s), 5.49 (1H, m), 7.14 (1H, t, J=8.2Hz), and 7.20-7.48 (5H, m), 7.55 (1H, t, J=8.2Hz), 7.93 (1H, d, J=8.0Hz), 8.72 (1H, d, J=8.6Hz). ultimate analysis (C
23H
26N
2O
40.2H
2O) calculated value: C, 69.40; H, 6.68; N, 7.04 measured values: C, 69.42; H, 6.58; N, 7.06.
Preparation example 23 cyclohexyl-(2-(aminomethyl carbamyl) phenyl) ketone bromate 13
The compound 12 that obtains with above-mentioned preparation example is according to preparation example 3 described method synthesising title compounds.Mp.193-196 ℃ of .IR ν
Max(KBr): 3432,1702,1645,1605,1588,1533cm
-1. ultimate analysis (C
15H
21BrN
2O
20.4H
2O) calculated value: C, 51.70; H, 6.31; Br, 22.93; N, 8.04 measured values: C, 51.86; H, 6.05; Br, 22.86; N, 8.04.
Preparation example 24 cyclohexyl-(2-(N '-(tolyl) urea groups methylamino formyl) phenyl) ketone 14a
With cyclohexyl-(2-(aminomethyl carbamyl) phenyl) ketone bromate 13 and toluene diisocyanate, according to the method synthesising title compound of preparation example 5.Mp：192-193℃。IR ν
Max(KBr): 3328,1669,1644,1594,1583,1559,1518cm
-1.NMR (CDCl
3+ CD
3OD) δ: 1.05-1.52 (5H, m), 1.62-1.89 (5H, m), 2.32 (3H, s), 4.02 (2H, s), 6.85 (1H, d, J=6.0Hz), 7.09-7.31 (4H, m), 7.55 (1H, m), 7.95 (1H, d, J=9.6Hz), 8.65 (1H, d, J=8.6Hz). ultimate analysis (C
23H
27N
2O
30.2H
2O) calculated value: C, 69.57; H, 6.95; N, 10.58 measured values: C, 69.37; H, 6.85; N, 10.53.
Preparation example 25 cyclohexyl-(2-(N '-(m-trifluoromethylphenyl) urea groups methylamino formyl) phenyl) ketone 14b
With cyclohexyl-(2-(aminomethyl carbamyl) phenyl) ketone bromate 13 and-(trifluoromethyl) phenyl isocyanate, according to the method synthesising title compound of preparation example 5.Mp：207-209℃。IR ν
Max(KBr): 3343,1661,1605,1581,1565,1524cm
-1.NMR (CDCl
3+ CD
3OD) δ: 1.13 (1H, m), 1.23-1.48 (4H, m), 1.65-1.89 (5H, m), 3.28 (1H, m), 4.11 (2H, s), 7.10-7.41 (3H, m), 7.48-7.68 (2H, m), 7.71 (1H, s), 7.90 (1H, d, J=8.2Hz), 8.68 (1H, d, J=8.6Hz). ultimate analysis (C
23H
24F
3N
3O
3) calculated value: C, 61.74; H, 5.41; N, 9.39 measured values: C, 61.70; H, 5.45; N, 9.40.
Preparation example 26 cyclohexyl-(2-(N '-(-(allyl oxygen phosphinylidyne) phenyl) urea groups methylamino formyl) phenyl) ketone 14c
With cyclohexyl-(2-(aminomethyl carbamyl) phenyl) ketone bromate (13) and-(allyl oxygen phosphinylidyne) phenyl isocyanate, according to the method synthesising title compound of preparation example 5.Mp：188-190℃。IR ν
Max(KBr): 3335,1720,1660,1582,1557,1524cm
-1.NMR (CDCl
3) δ: 1.03-1.52 (5H, m), 1.53-1.91 (5H, m), 3.23 (1H, m), 4.17 (2H, d, J=6.0Hz), 4.79 (2H, d, J=5.8Hz), 5.15-5.48 (2H, m), 5.82-6.13 (2H, m), 7.12 (1H, m), 7.31 (1H, t, J=13.5Hz), 7.49 (1H, m), 7.70 (1H, m), 7.96 (1H, m), 8.69 (1H, d, J=9.4Hz), 12.18 (1H, s). ultimate analysis (C
26H
29N
3O
5) calculated value: C, 67.37; H, 6.31; N, 9.07 measured values: C, 67.53; H, 6.36; N, 9.12.
Preparation example 27 N-(2-iodophenyl)-2-(benzyloxy carbon acylamino) ethanamide 21
Ice-cooled down while stirring to N,N-DIMETHYLACETAMIDE (32ml) in the interpolation Phosphorus Oxychloride (2.2ml, 24mmol), imidazoles (2.7g, 40mmol), N-benzyloxy phosphinylidyne glycine (5.0g, 24mmol).Stir after 5 minutes, drip 2-Iodoaniline (4.4g, DMA 20mmol) (10ml) solution.This reaction solution stirred 3 hours at 50 ℃.Place the cooling back and in reaction solution, add water and ethyl acetate, transfer to pH=9, water layer ethyl acetate extraction 2 times with saturated sodium bicarbonate aqueous solution.Organic layer saturated common salt water washing is with concentrating behind the anhydrous magnesium sulfate drying.Add isopropyl ether (40ml) in the residue, the solid of separating out is leached, obtain target compound (7.10g).Yield 86%.NHR(CDCl
3)δ：4.06(2H，d，J＝5.8Hz)，5.19(2H，s)，5.44(1H，brs)，6.80-6.91(1H，m)，7.20-7.45(6H，m)，7.76(1H，d，J＝8.0Hz)，8.12(1H，brs)，8.21(1H，d，J＝8.0Hz).
Preparation example 28 2-amino-N-(2-iodophenyl) ethanamide bromate 22
With compound 21 (6.15g), according to preparation example 3 described method synthesising title compounds (5.2g).Yield 96%.NHR(CDCl
3)δ：3.94(2H，s)，6.99-7.07(1H，m)，7.37-7.45(1H，m)，7.55(1H，d，J＝8.2Hz)，7.92(1H，d，J＝8.0Hz).
Preparation example 29 N-(2-iodophenyl)-2-(tolyl urea groups between 3-) ethanamide 23
With a compound 2 (2.67g) and a toluene diisocyanate (0.96ml), according to preparation example 5 described method synthesising title compounds (3.05g).Yield 100%.NHR(DMSO-d
6)δ：2.25(3H，s)，3.95(2H，d，J＝5.4Hz)，6.48-6.55(1H，m)，6.73(1H，d，J＝6.8Hz)，6.93-7.45(5H，m)，7.61(1H，dd，J＝1.4Hz，8.1Hz)，7.88(1H，dd，J＝1.4Hz，8.0Hz)，8.79(1H，s)，9.45(1H，s).
Preparation example 30 ((2-iodophenyl)-(2-(tolyl urea groups between 3-) acetyl) amino) tert.-butyl acetate 24
In room temperature to N-(2-iodophenyl)-2-(tolyl urea groups between 3-) ethanamide (1.02g, 2.5mmol) DMSO (5ml) solution in add potassiumiodide (83mg, 0.2mmol), bromination four positive fourth ammonium (81mg, 0.1mmol), bromo-acetic acid tert-butyl (0.55ml, 3.75mmol), salt of wormwood (1.04g, 7.5mmol), stirring at room 2.25 hours.In reaction solution, add water and ethyl acetate, transfer to pH=2 with 2N hydrochloric acid.Water layer ethyl acetate extraction 2 times.Organic layer is with 0.1N hydrochloric acid, water, saturated common salt water washing, with concentrating behind the anhydrous magnesium sulfate drying.Add isopropyl ether in the residue, the solid of separating out is leached, obtain target compound (1.20g).Yield 92%.NHR(CDCl
3)δ：1.45(9H，s)，2.35(3H，s)，3.49(1H，d，J＝17.6Hz)，3.65(1H，dd，J＝4.4Hz，17.6Hz)，3.88(1H，dd，J＝4.4Hz，17.6Hz)，4.92(1H，d，J＝17.6Hz)，5.78-5.82(1H，m)，6.59(1H，brs)，6.87(1H，d，J＝7.4Hz)，7.14-7.48(5H，m)，7.69(1H，d，J＝7.8Hz)，7.95(1H，d，J＝8.2Hz).
Preparation example 31 ((2-trimethylammonium stannyl phenyl)-(2-(tolyl urea groups between 3-) acetyl) amino) tert.-butyl acetate 25
In room temperature to ((2-iodophenyl)-(2-(tolyl urea groups between 3-) acetyl) amino) tert.-butyl acetate (52mg, 0.1mmol) toluene (2ml) solution in add trans-benzyl chloride two (triphenyl phosphine) palladium (3.8mg, 5 μ mol), tetraethylammonium chloride (3mg, 20 μ mol), hexa methyl ditin (50mg, 0.15mmol), stirred 1 hour at 85 ℃, stirred 30 minutes at 100 ℃.In reaction solution, add frozen water, stirring, water layer ethyl acetate extraction 2 times.Organic layer is with the saturated common salt water washing, with concentrating behind the anhydrous magnesium sulfate drying.Residue is refining with silica gel column chromatography, obtains target compound (35mg).Yield 64%.NHR(CDCl
3)δ：0.29(9H，s)，1.43(9H，s)，2.29(3H，s)，3.56(1H，d，J＝16.8Hz)，3.80(2H，s)，4.79(1H，d，J＝16.8Hz)，6.00(1H，brs)，6.80-7.61(9H，m).
R
4＝
a：X＝2-F，b：X＝4-CF
3，c：X＝4-CN，
Preparation example 32 N-(2-tributyl stannyl phenyl)-2-(benzyloxy carbon acylamino) ethanamide 27
In room temperature to N-(2-iodophenyl)-2-(benzyloxy carbon acylamino) ethanamide (compound 21) (4.1g, 0.01mol) methylene dichloride (80ml) solution in add dichloro diacetonitrile palladium (190mg, 0.25mmol), six dibutyltin dilaurates (6.0ml, 0.012mol), in stirred overnight at room temperature.In reaction solution, add 50% potassium fluoride aqueous solution, stirred the elimination precipitate 30 minutes.After this operation repeated once again, organic layer saturated common salt water washing was with concentrating behind the anhydrous magnesium sulfate drying.Residue is refining with silica gel column chromatography, obtains target compound (4.4g).Yield 77%.NHR(CDCl
3)δ：0.83-1.65(27H，m)，4.03(2H，d，J＝5.6Hz)，5.16(2H，s)，5.40(1H，brs)，7.10-7.48(1H，m)，7.71(1H，d，J＝8.0Hz).
Preparation example 33 N-(2-(2-fluorobenzoyl) phenyl)-2-(benzyloxy carbon acylamino) ethanamide 28a
Room temperature to the 2-fluorobenzoyl chloride (208 μ l, add in chloroform 1.74mmol) (20ml) solution dichloro diacetonitrile palladium (15mg, 0.044mmol).(1g, chloroform 1.74mmol) (3ml) solution stirred 35 minutes at 50 ℃ to add N-(2-tributyl stannyl phenyl)-2-(benzyloxy carbon acylamino) ethanamide subsequently.Interpolation dichloro diacetonitrile palladium (15mg, 0.044mmol), restir 10 minutes.After the cooling, in reaction solution, add 50% potassium fluoride aqueous solution, stirred the elimination precipitate 30 minutes.After this operation repeated once again, organic layer was with the saturated common salt water washing, with concentrating behind the anhydrous magnesium sulfate drying.Residue is refining with silica gel column chromatography, obtains target compound (570mg).Yield 80%.NHR(CDCl
3)δ：4.12(2H，d，J＝6.0Hz)，5.19(2H，s)，5.50(1H，brs)，7.05-7.66(7H，m)，8.74(1H，d，J＝8.2Hz).
Preparation example 34 N-(2-(4-trifluoromethyl benzoyl) phenyl)-2-(benzyloxy carbon acylamino) ethanamide 28b
With ((2-trimethylammonium stannyl phenyl)-(2-(tolyl urea groups between 3-) acetyl) amino) tert.-butyl acetate (1.0g) and 4-trifluoromethyl benzoyl chloride (364mg), according to the synthesis method of compound 28a, synthesising title compound (592mg).Yield 74%.NHR(CDCl
3)δ：4.10(2H，d，J＝6.0Hz)，5.18(2H，s)，5.50(1H，brs)，7.08-7.67(8H，m)，7.76(4H，s)，8.68(1H，d，J＝8.2Hz).
Preparation example 35 N-(2-(4-cyano group benzoyl) phenyl)-2-(benzyloxy carbon acylamino) ethanamide 28c
With ((2-trimethylammonium stannyl phenyl)-(2-(tolyl urea groups between 3-) acetyl) amino) tert.-butyl acetate (1.0g) and 4-cyano-benzoyl chloride (289mg),, synthesized title compound (551mg) according to the synthesis method of compound 28a.Yield 76%.NHR(CDCl
3)δ：4.09(2H，d，J＝6.0Hz)，5.18(2H，s)，5.50(1H，brs)，7.08-7.69(8H，m)，7.74(2H，d，J＝8.6Hz)，7.80(2H，d，J＝8.6Hz)，8.68(1H，d，J＝8.2Hz).
Preparation example 36 N-(2-(diamantane-1-phosphinylidyne) phenyl)-2-(benzyloxy carbon acylamino) ethanamide 28d
With ((2-trimethylammonium stannyl phenyl)-(2-(tolyl urea groups between 3-) acetyl) amino) tert.-butyl acetate (2.5g) and diamantane-1-carbonyl chloride (866mg),, synthesized title compound (110mg) according to the synthesis method of compound 28a.Yield 6%.NHR (CDCl
3) δ: 1.72 (6H, s), 2.00 (6H, s), 2.06 (3H, s), 4.00 (2H, d, J=5.8Hz), 5.20 (2H, s), 5.44 (1H, brs), 7.09-7.68 (8H, m), 8.28 (2H, d, J=8.7Hz), 9.57 (1H, brs). preparation example 37 N-(2-(1-oxo-2-propyl group amyl group) phenyl)-2-(benzyloxy carbon acylamino) ethanamide 28e
With ((2-trimethylammonium stannyl phenyl)-(2-(tolyl urea groups between 3-) acetyl) amino) tert.-butyl acetate (2.5g) and 2-n-propyl n-amyl chloride (710mg),, synthesized title compound (990mg) according to the synthesis method of compound 28a.Yield 55%.NHR(CDCl
3)δ：0.88(6H，t，J＝7.0Hz)，1.16-1.84(8H，m)，3.43-3.58(1H，m)，4.10(2H，d，J＝5.4Hz)，5.19(2H，s)，5.44(1H，brs)，7.10-7.62(7H，m)，7.94(1H，d，J＝8.2Hz)，8.73(1H，d，J＝8.2Hz).
Preparation example 38 2-amino-N-(2-(2-fluorobenzoyl) phenyl) ethanamide hydrobromate 29a
With compound 28a (530mg),, synthesized title compound (432mg) according to preparation example 3 described methods.Yield 94%.NHR(CD
3OD)δ：3.88(2H，s)，6.99-7.07(1H，m)，7.18-7.70(7H，m)，8.20(1H，d，J＝8.0Hz).
Preparation example 39 2-amino-N-(2-(4-trifluoromethyl benzoyl) phenyl) ethanamide hydrobromate 29b
With compound 28b (550mg),, synthesized title compound (450mg) according to preparation example 3 described methods.Yield 93%.NHR(CD
3OD)δ：3.90(2H，s)，7.19-7.67(3H，m)，7.76(2H，d，J＝8.0Hz)，7.86(2H，d，J＝8.0Hz)，8.19(1H，d，J＝8.2Hz).
Preparation example 40 2-amino-N-(2-(4-cyano group benzoyl) phenyl) ethanamide hydrobromate 29c
With compound 28c (542mg),, synthesized title compound (484mg) according to preparation example 3 described methods.Yield 100%.
NHR(CD
3OD)δ：3.76(2H，s)，7.29-7.88(3H，m)，7.89(4H，s)。
Preparation example 41 2-amino-N-(2-(diamantane-1-phosphinylidyne) phenyl) ethanamide hydrobromate 29d
With compound 28d (100mg),, synthesized title compound (61mg) according to preparation example 3 described methods.Yield 69%.NHR(CD
3OD)δ：1.75(6H，s)，1.97(6H，s)，2.02(3H，s)，3.83(2H，s)，7.22-7.58(4H，m).
Preparation example 42 2-amino-N-(2-(1-oxo-2-propyl group amyl group) phenyl) ethanamide hydrobromate 29e
With compound 28e (770mg),, synthesized title compound (522mg) according to preparation example 3 described methods.Yield 78%.NHR(CD
3OD)δ：0.88(6H，t，J＝7.2Hz)，1.19-1.83(8H，m)，3.58-3.73(1H，m)，4.00(2H，s)，7.26-7.69(2H，m)，8.1?4(1H，dd，J＝1.6Hz，8.2Hz)，8.56(1H，d，J＝8.2Hz).
Preparation example 43 3-(3-(2-(2-fluorobenzoyl) phenyl amino formyl methyl) urea groups) phenylformic acid allyl ester 30a
With isocyanic ester and compound 29a (432mg) from 3-aminobenzoic allyl propionate hydrochloride (261mg) and triphosgene (145mg) preparation is raw material, according to the method for preparation example 5, has synthesized title compound (391mg).Yield 67%.NHR(CDCl
3)δ：4.19(2H，d，J＝5.4Hz)，4.78(2H，d，J＝5.4Hz)，5.21-5.44(2H，m)，5.79-6.10(2H，m)，7.03-7.94(12H，m)，8.69(1H，d，J＝8.2Hz).
Preparation example 44 3-(3-(2-(4-trifluoromethyl benzoyl) phenyl amino formyl methyl) urea groups) phenylformic acid allyl ester 30b
With compound 29b (450mg) is raw material, according to the method for preparation example 5, has synthesized title compound (343mg).Yield 65%.NHR(CDCl
3)δ：4.14(2H，d，J＝5.7Hz)，4.76(2H，d，J＝5.4Hz)，5.22-5.41(2H，m)，5.92-6.05(2H，m)，7.06-7.76(11H，m)，7.90(1H，s)，8.57(1H，d，J＝84Hz)，11.31(1H，s).
Preparation example 45 3-(3-(2-(4-cyano group benzoyl) phenyl amino formyl methyl) urea groups) phenylformic acid allyl ester 30c
With compound 29c (472mg) is raw material, according to the method for preparation example 5, has synthesized title compound (438mg).Yield 69%.NHR(CDCl
3)δ：4.13(2H，d，J＝5.7Hz)，4.79(2H，d，J＝5.4Hz)，5.22-5.44(2H，m)，5.79-6.12(2H，m)，7.06-7.80(11H，m)，7.89(1H，s)，8.58(1H，d，J＝8.4Hz).
Preparation example 46 3-(3-(2-(diamantane-1-phosphinylidyne) phenyl amino formyl methyl) urea groups) phenylformic acid allyl ester 30d
With compound 29d (61mg) is raw material, according to the method for preparation example 5, has synthesized title compound (44mg).Yield 55%.NHR(CDCl
3)δ：1.63(9H，s)，1.90(6H，s)，4.05(2H，d，J＝5.8Hz)，4.81(2H，d，J＝6.0Hz)，5.23-5.45(2H，m)，5.81-6.12(2H，m)，7.07-7.98(12H，m)，8.21(1H，d，J＝8.0Hz).
Preparation example 47 3-(3-(2-(1-oxo-2-propyl group amyl group) phenyl amino formyl methyl) urea groups) phenylformic acid allyl ester 30e
With compound 29e (522mg) is raw material, according to the method for preparation example 5, has synthesized title compound (321mg).Yield 43%.NHR(CDCl
3)δ：0.83(6H，t，J＝7.0Hz)，1.12-1.78(8H，m)，3.41-3.56(1H，m)，5.22-5.45(2H，m)，5.84-6.12(2H，m)，7.10-7.98(12H，m)，8.71(1H，d，J＝8.4Hz).
Preparation example 48 N-(2-(thiophene-2-phosphinylidyne) phenyl)-2-(benzyloxy carbon acylamino) acetyl 34
With compound 33,, synthesized title compound according to the synthesis method of compound 21.Mp.115-116.5 ℃ of .IR ν
Max(KBr): 3274,1716,1671,1619,1601,1579,1514cm
-1.NMR (CDCl
3) δ: 4.04 (2H, d, J=6.0Hz), 5.18 (2H, s), and 5.44-5.60 (1H, m), 7.15-7.50 (7H, m), and 7.56-7.62 (2H, m), 7.75 (1H, dd, J=4.8Hz, 0.9Hz), 7.84 (1H, dd, J=7.8Hz, 1.2Hz), 8.55 (1H, d, J=8.1Hz), 10.80 (1H, s). ultimate analysis (C
21H
18N
2O
4S) calculated value: C, 63.95; H, 4.60; N, 7.10; S.13 measured value: C, 63.97; H, 4.70; N, 7.17; S, 8.03.
Preparation example 49 2-amino-N-(2-(thiophene-2-phosphinylidyne) phenyl) ethanamide hydrobromate 35
With compound 34,, synthesized title compound according to preparation example 3 described methods.NMR(CDCl
3＋CD
3OD)δ：5.31(2H，s)，7.08-7.24(2H，m)，7.44-7.54(2H，m)，7.66(1H，d，J＝7.8Hz)，7.74(1H，dd，J＝5.0Hz，1.2Hz)，8.09(1?H，dd，J＝8.2Hz，1.8Hz)，10.35(1H，s).
Preparation example 50 N-(2-(thiophene-2-phosphinylidyne) phenyl)-2-(tolyl urea groups between 3-) ethanamide 36a
With compound 35,, synthesized title compound according to preparation example 15 described methods.Mp：208-210℃。IR ν
Max(KBr): 3337,1687,1638,1609,1580,1563,1518cm
-1.NMR (DMSO-d
6) δ: 2.22 (3H, s), 3.79 (2H, d, J=5.2Hz), 6.50 (2H, t, J=10.8Hz), 6.72 (1H, dd, J=2.6Hz, 0.8Hz), 7.04-7.32 (5H, m), and 7.52-7.70 (3H, m), 7.94 (1H, d, J=8.2Hz), 8.04-8.10 (1H, m), 8.76 (1H, s), 10.33 (1H, s). ultimate analysis (C
21H
19N
3O
3S) calculated value: C, 64.11; H, 4.87; N, 10.68; S, 8.15 measured values: C, 64.09; H, 4.92; N, 10.74; S, 8.05.
Preparation example 51 3-(3-(2-(thiophene-2-phosphinylidyne) phenyl amino formyl methyl) urea groups) phenylformic acid allyl ester 36b
With compound 35,, synthesized title compound according to preparation example 15 described methods.Mp：140-141℃IRν
max(KBr)：3284，1714，1689，1648，1618，1584，1560，1520cm
-1.NMR(CDCl
3)δ：4.09(2H，d，J＝5.6Hz)，4.77(2H，dt，J＝5.4Hz，1.4Hz)，5.25(1H，dd，J＝10.2Hz，1.2Hz)，5.37(1H，dd，J＝17.2Hz，1.4Hz)，5.85-6.10(2H，m)，7.05-7.30(3H，m)，7.50-7.80(7H，m)，7.91(1H，m)，8.45(1H，dd?J＝8.2Hz，0.8Hz)，10.71(1H，s)。Ultimate analysis (C
24H
21N
2O
5S) calculated value: C, 62.19; H, 4.57; N, 9.07; S, 6.92 measured values: C, 62.13; H, 4.74; N, 9.00; S, 6.81.
Preparation example 52 N-(2-(4-methoxybenzoyl) phenyl)-2-(benzyloxy carbon acylamino) ethanamide 40
With compound 39,, synthesized title compound according to the synthesis method of compound 21.Mp.97-98℃。IR ν
Max(KBr): 3342,1687,1624,1583,1513cm
-1.NMR (CDCl
3) δ: 3.89 (3H, s), 4.05 (2H, d, J=6.0Hz), 5.1 6 (2H, s), 5.55-5.58 (1H, m), and 6.93-6.98 (2H, m), 7.09-7.14 (1H, m), and 7.30-7.42 (5H, m), 7.52-7.57 (2H, m), and 7.69-7.72 (2H, m), 8.55 (1H, d, J=7.5Hz), 11.06 (1H, s). ultimate analysis (C
24H
22N
2O
5) calculated value: C, 68.88; H, 5.30; N, 6.69 measured values: C, 68.91; H, 5.34; N, 6.72.
Preparation example 53 2-amino-N-(2-(4-methoxybenzoyl) phenyl) ethanamide hydrobromate 41
With compound 42,, synthesized title compound according to the method described in the preparation example 3.NMR(D
2O)δ：3.67(2H，s)，3.92(3H，s)，7.05-7.10(2H，m)，7.40-7.78(6H，m)
Preparation example 54 N-(2-(4-methoxybenzoyl) phenyl)-2-(tolyl urea groups between 3-) ethanamide 42a
With compound 41,, synthesized title compound according to preparation example 15 described methods.Be amorphous powder.IRν
max(KBr)：3313，2925，2855，1654，1597，1581，1559cm
-1.NMR(CDCl
3)δ：2.18(3H，s)，3.84(3H，s)，4.02(2H，d，J＝6.0Hz)，6.10(1H，t，J＝6.0Hz)，6.75-6.90(3H，m)，7.03-7.10(4H，m)，7.45-7.68(5H，m)，8.44(1H，d，J＝7.2Hz)，10.94(1H，s).
Preparation example 55 3-(3-(2-(4-methoxybenzoyl) phenyl amino formyl methyl) urea groups) phenylformic acid allyl ester 42b
With compound 41,, synthesized title compound according to preparation example 15 described methods.Mp.167-169 ℃ of .IR ν
Max(KBr): 3371,3275,1715,1690,1641,1591,1566,1525cm
-1.NMR (CDCl
3) δ: 3.86 (3H, s), 4.07 (2H, d, J=6.0Hz), 4.78 (2H, dt, J=5.7Hz, 1.2Hz), 5.24-5.28 (1H, m), 5.35-5.41 (1H, m), and 5.94-6.07 (1H, m), 6.43 (1H, t, J=5.4Hz), 6.87-6.95 (2H, m), 7.07-7.12 (1H, m), 7.23-7.29 (1H, m), 7.49-7.55 (2H, m), 7.62-7.67 (3H, m), 7.75-7.78 (1H, m), 7.90-7.91 (1H, m), 8.35 (1H, s), 8.51 (1H, d, J=7.5Hz), 10.95 (1H, s). ultimate analysis (C
27H
25N
3O
6) calculated value: C, 66.52; H, 5.17; N, 8.62 measured values: C, 66.37; H, 5.29; N, 8.58.
The another kind of synthesis method I of preparation example 56 2-(benzyloxy phosphinylidyne glycyl amino) benzophenone (compound 6b)
(1) 3-(methoxy phosphinylidyne methyl urea groups) phenylformic acid allyl ester 45
With triphosgene (2.5g, 8.42mmol) and 3-aminobenzoic allyl propionate hydrochloride (4.0g, methylene dichloride 18.7mmol) (80ml) suspension is cooled to-20 ℃, (9.64ml 69.2mmol), stirred 30 minutes to drip triethylamine.To wherein add glycine methyl ester hydrochloride (2.82g, 22.44mmol).(3.75ml 18.7mmol), stirred 2.5 hours at-20 ℃ to drip triethylamine subsequently.In reaction solution, add frozen water, stirring, water layer ethyl acetate extraction 2 times.Organic layer saturated common salt water washing with concentrating behind the anhydrous magnesium sulfate drying, obtains target compound (5.27g).Yield 96%.NHR(CDCl
3)δ：3.76(3H，s)，4.08(2H，s)，4.80(2H，d，J＝5.5Hz)，5.23-5.45(2H，m)，5.92-6.12(2H，m)，7.28-7.38(1H，m)，7.67-7.90(3H，m).
(2) (3-allyl oxygen phosphinylidyne phenyl) Ureidoacetic acid 46
(5.27g adds 2N hydrochloric acid (37.4ml) in THF 18.7mmol) (27ml) solution, reflux and stirred 2.5 hours to 3-(methoxy phosphinylidyne methyl urea groups) phenylformic acid allyl ester.After the cooling, add water and saturated sodium bicarbonate aqueous solution in reaction solution, water layer transfers to after the pH=8, uses ethyl acetate extraction.Add concentrated hydrochloric acid in the water layer and transfer to pH=1, use ethyl acetate extraction.Organic layer is with the saturated common salt water washing, with concentrating behind the anhydrous magnesium sulfate drying.Residue toluene crystallization obtains target compound (3.66g).Yield 70%.NHR(DMSO-d
6)δ：3.80(2H，d，J＝5.9Hz)，4.79(2H，d，J＝5.4Hz)，5.24-5.47(2H，m)，5.95-6.16(2H，m)，6.41(1H，t，J＝5.9Hz)，7.39(1H，t，J＝7.8Hz)，7.50-7.65(2H，m)，8.14(1H，s)，9.08(1H，s).
(3) 2-(allyl oxygen phosphinylidyne phenyl glycyl amino) benzophenone 6b
The cooling under (10～0 ℃) while stirring to DMA (40ml) in the interpolation Phosphorus Oxychloride (2.07ml, 22.64mmol) and imidazoles (1.54g, 22.64mmol).(3.0g, N,N-DIMETHYLACETAMIDE 10.78mmol) (10ml) solution stirred 10 minutes down ice-cooled to drip (3-allyl oxygen phosphinylidyne phenyl) Ureidoacetic acid.Drip 2-Uvinul A Plus (2.34g, DMA 11.86mmol) (5ml) solution subsequently.This reaction solution stirred 5.5 hours at 50 ℃.After the cooling, in reaction solution, add water and ethyl acetate, transfer to pH=9, the water layer ethyl acetate extraction with saturated sodium bicarbonate aqueous solution.Organic layer is with the saturated common salt water washing, with concentrating behind the anhydrous magnesium sulfate drying.Residue toluene crystallization obtains target compound (3.63g).Yield 74%.
The another kind of synthesis method II of preparation example 57 2-(allyl oxygen phosphinylidyne phenyl glycyl amino) benzophenone (compound 6b)
(1) under nitrogen gas stream,, in DMF (25ml) suspension of N '-phosphinylidyne diimidazole (5.69g, 1.5 equivalents), dripping with ice-cooled raw material (5.00g) DMF (20ml) solution with 30 minutes below 5 ℃ to N.After same temperature stirs 1 hour 30 minutes, add glycine methyl ester hydrochloride 3.53g (1.2 equivalent), stirring at room 2 hours.
In the mixture with this reaction solution impouring 1N hydrochloric acid (50ml) and ethyl acetate (50ml), separatory.Organic layer water (25ml) washing 2 times, water layer extracts with ethyl acetate (25ml).With organic layer merge, with concentrating under reduced pressure behind the anhydrous sodium sulfate drying, obtain the crystallinity residue (6.55g, 95.8%) of compound 45.
(2) under nitrogen gas stream, down in DMF (40ml) suspension of glycine (9.13g, 1.3 equivalents), drip trimethylsilyl chloride (16.0ml, 1.35 equivalents) ice-cooled, stirring at room 1.5 hours with 6 fens clock times.Stirred 0.5 hour at 40 ℃.Then, stir down, obtain O-silyl glycine reactant liquid ice-cooled.
Under nitrogen gas stream, ice-cooled down, below 5 ℃ with 10 fens clock times to N, drip DMF (60ml) solution of raw material (20.00g) in DMF (80ml) suspension of N '-phosphinylidyne diimidazole (22.77g, 1.5 equivalents), wash with DMF (10ml).After same temperature stirs 1.5 hours, add above-mentioned O-silyl glycine reactant liquid, stirring at room 2 hours.
In the mixture of this reaction solution impouring ethyl acetate (300ml), frozen water (200ml), IN HCl (200ml) and salt (60g), separatory.Organic layer water (200ml), saturated sodium bicarbonate aqueous solution (200ml), saturated sodium bicarbonate aqueous solution (100ml)+water (100ml) washing.Water layer is with ethyl acetate 200ml, then with 100ml back extraction successively.
Merge hydrogen-carbonate soda layer, add ethyl acetate (260ml), under agitation drip concentrated hydrochloric acid (10ml), separatory.Organic layer washs 2 times with 10% salt solution.Water layer ethyl acetate (130ml) back extraction.Merge organic layer, in dry back concentrating under reduced pressure, add toluene (200ml) concentrating under reduced pressure again with anhydrous sodium sulphate, obtain the pulpous state liquid of compound 46, cooling standing over night after-filtration with toluene (20ml) washing 2 times, obtains the crystallization 21.7g (83.3%) of compound 46.With this compound 46, handle according to the method the same with preparation example 57, obtain compound 6b.
Preparation example 58 uncle's N-fourth oxygen phosphinylidyne-2-Iodoanilines 47
Room temperature to Iodoaniline (11.0g, 0.05mol) add in the solution pyridine (10.1ml, 0.10mol) and Dimethylamino pyridine (610mg, 5mmol).(26.6ml, 0.125mol) backflow was stirred 6 hours to drip the oxalic acid di tert butyl carbonate.After the cooling, reaction solution dilutes with ethyl acetate, after frozen water, adds 2N hydrochloric acid and transfers to PH=1.Ethyl acetate extraction 2 times of this water layer.Organic layer saturated common salt water washing is with concentrating behind the anhydrous magnesium sulfate drying.This residue is dissolved in the methyl alcohol (200ml), with the ice-cooled aqueous sodium hydroxide solution (50ml) that adds down 2N while stirring.After 2 hours, decompression steams methyl alcohol in stirring at room.Reaction solution dilutes with methylene dichloride, after frozen water, adds 2N hydrochloric acid and transfers to PH=1.Ethyl acetate extraction 2 times of this water layer.Organic layer is with the saturated common salt water washing, with concentrating behind the anhydrous magnesium sulfate drying.Residue is refining with silica gel column chromatography, obtains target compound (8.54g).Yield 54%.NHR(CDCl
3)δ：1.42(9H，s)，6.71-6.81(1H，m)，6.82(1H，brs)，7.26-7.36(1H，m)，7.75(1H，dd，J＝1.2Hz，8.0Hz)，8.05(1H，dd，J＝1.6Hz，8.2Hz).
Preparation example 59 uncle's N-fourth oxygen phosphinylidyne-2-(trimethylammonium stannyl) aniline 48
In room temperature to uncle's N-fourth oxygen phosphinylidyne-2-Iodoaniline (3.20g, 0.01mol) toluene (65ml), solution in add trans-benzyl chloride two (triphenyl phosphine) palladium (380mg, 5 μ mol), tetraethylammonium chloride (330mg, 20 μ mol), hexa methyl ditin (5.1g, 0.015mmol), stirred 2.5 hours at 95 ℃.After placing cooling, in reaction solution, add frozen water, stirring, the elimination precipitate.The water layer ethyl acetate extraction.Organic layer saturated common salt water washing is with concentrating behind the anhydrous magnesium sulfate drying.Residue is refining with silica gel column chromatography, obtains target compound (2.46g).Yield 69%.NHR(CDCl
3)δ：0.34(9H，s)，1.51(9H，s)，6.28(1H，brs)，7.07-7.17(1H，m)，7.22-7.43(2H，m)，7.52(1H，d，J＝8.6Hz).
Preparation example 60 2-(N-(benzyloxy phosphinylidyne) piperidines-4-phosphinylidyne)-N '-uncle's fourth oxygen carbonyl aniline 49
(1.10g 4.18mmol) is dissolved in the thionyl chloride (1.23ml), refluxes and stirs 20 minutes N-(benzyloxy phosphinylidyne) piperidines-4-carboxylic acid.Decompression steams superfluous thionyl chloride, and residue is dissolved in the toluene.Room temperature to wherein add dichloro diacetonitrile palladium (73mg, 0.209mmol).(1.50g 4.18mmol), stirred 45 minutes at 55 ℃ to add uncle's N-fourth oxygen phosphinylidyne-2-(trimethylammonium stannyl) aniline subsequently.After placing cooling, in reaction solution, add frozen water, stirring, water layer ethyl acetate extraction 2 times.Organic layer is with the saturated common salt water washing, with concentrating behind the anhydrous magnesium sulfate drying.Residue is refining with silica gel column chromatography, obtains target compound (1.49g).Yield 81%.NHR(CDCl
3)δ：1.53(9H，s)，1.63-1.95(4H，m)，2.85-3.06(2H，m)，3.37-3.58(1H，m)，4.16-4.38(2H，m)，5.15(2H，s)，6.99-7.08(1H，m)，7.36(5H，s)，7.48-7.57(1H，m)，7.86(1H，dd，J＝1.2Hz，8.2Hz)，8.51(1H，dd，J＝1.0Hz，8.2Hz).
Preparation example 61 2-(N-(benzyloxy phosphinylidyne) piperidines-4-phosphinylidyne) aniline 50
At room temperature to 2-(N-(benzyloxy phosphinylidyne) piperidines-4-phosphinylidyne)-(130g adds phenylmethylether (2.0ml) in methylene dichloride 3.0mmol) (6.5ml) solution to N ' uncle fourth oxygen carbonyl aniline.Subsequently, at the ice-cooled trifluoroacetic acid (13.0ml) that drips while stirring down, stirred 1 hour in this temperature.Reaction solution dilutes with ethyl acetate, after frozen water, neutralizes with saturated sodium bicarbonate aqueous solution.Ethyl acetate extraction 2 times of this water layer.Organic layer is with the saturated common salt water washing, with concentrating behind the anhydrous magnesium sulfate drying.Residue is refining with silica gel column chromatography, obtains target compound (987mg).Yield 99%.NHR(CDCl
3)δ：1.69-1.96(4H，m)，2.83-3.08(2H，m)，3.35-3.53(1H，m)，4.17-4.39(2H，m)，5.15(2H，s)，6.30(2H，brs)，6.61-6.70(2H，m)，7.23-7.39(1H，m)，7.36(5H，s)，7.73(1H，d，J＝8.2Hz).
Preparation example 62 3-(3-(2-(N-(benzyloxy phosphinylidyne) piperidines-4-phosphinylidyne) phenyl amino formyl methyl) urea groups) phenylformic acid allyl ester 51
With 2-(N-(benzyloxy phosphinylidyne) piperidines-4-phosphinylidyne) aniline (677mg) and 2-(benzyloxy phosphinylidyne glycyl amino) benzophenone (compound 46) is raw material (556mg), according to the synthesis method of chemical combination 6b, has synthesized title compound (780mg).Yield 65%.NHR(DMSO-d
6)δ：1.13-1.39(2H，m)，1.54-1.79(2H，m)，2.80-3.06(2H，m)，3.52-3.69(1H，m)，3.74-3.98(2H，m)，3.88(2H，d，J＝6.0Hz)，3.76(2H，d，J＝5.2Hz)，5.06(2H，s)，5.20-5.43(2H，m)，5.90-6.13(1H，m)，6.83(1H，t，J＝6.0Hz)，7.18-7.68(10H，m)，8.05(1H，d，J＝7.8Hz)，8.15(1H，s)，8.45(1H，d，J＝7.8Hz)，9.28(1H，s)，11.60(1H，s).
Embodiment 1 2-(N-(tetramethyleneimine phosphinylidyne methyl)-N-(N '-(tolyl) urea groups methyl phosphinylidyne) amino) benzophenone 5a
Dimethyl formamide (5m1) solution stirring of acid amides 4a (300mg), acetobrom tetramethyleneimine (17.35mg), salt of wormwood (120mg) and the potassiumiodide (10mg) of preparation example 5 preparations is spent the night.After in the impouring water, the mixture ethyl acetate extraction.Steam solvent under extract washing, the decompression of dry (sodium sulfate) back.Residue acetonitrile recrystallization.Yield 53%, Mp:204-205 ℃.IR ν
Max(KBr): 3310,1655,1637,1560cm
-1.NMR (CDCl
3) δ: 1.81 (4H, m), 2.28 (3H, s), 3.34 (4H, m), 3.78 (1H, d, J=18.0Hz), 3.81 (1H, d, J=16.4Hz), 3.99 (1H, d, J=17.2Hz), 4.82 (1H, d, J=16.4Hz), 5.78 (1H, br.s), 6.80-7.79 (13H, m). ultimate analysis (C
29H
30N
4O
4)
Calculated value: C, 69.86; H, 6.06; N, 11.24
Measured value: C, 69.72; H, 6.17; N, 11.04.
Embodiment 2 2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N-(N '-(tolyl) urea groups methyl phosphinylidyne) amino) benzophenone 5b
As initial substance,, make target compound 5b with compound 4b with embodiment 1 the same carrying out.Yield 50%, Mp:183-184 ℃.IR ν
Max(KBr): 3344,1746,1658,1618,1561cm
-1.NMR (CDCl
3) δ: 1.39 (9H, s), 2.28 (3H, s), 3.65 (1H, d, J=17.8Hz), 3.77 (1H, d, J=17.8Hz), 4.01 (1H, d, J=17.4Hz), 4.64 (1H, d, J=17.4Hz), 5.90 (1H, br.s), 6.81-6.84 (1H, d, J=6.0Hz), and 6.95-7.81 (13H, m). ultimate analysis (C
29H
31N
3O
5)
Calculated value: C, 69.44; H, 6.23; N, 8.38
Measured value: C, 69.14; H, 6.28; N, 8.33.
Embodiment 3 2-(N-(cyclopropyl phosphinylidyne methyl)-N-(N '-(tolyl) urea groups methyl phosphinylidyne) amino) benzophenone 5c
As initial substance,, make target compound 5c with compound 4c with embodiment 2 the same carrying out.Yield 3.3%, Mp:114-118 ℃.IRν
max(KBr)：3391，1650，1611，1596，1556cm
-1.NMR(CDCl
3)δ：1.16(4H，m)，1.94(1H，br.s)，3.23(3H，s)，3.43-4.67(4H，m)，6.07(1H，br.s)，6.79(2H，d，J＝6.4Hz)，7.04-7.40(13H，m)，8.27(1H，s).
Embodiment 4 2-(N-(aminobenzyl)-N-(N '-(tolyl) urea groups methyl phosphinylidyne) amino) benzophenone 5d
Without the acetobrom tetramethyleneimine, and between using-(BOC-A amino) bromotoluene, carry out the N-alkylation according to the method the same with embodiment.Add 4N hydrogenchloride ethyl acetate solution in the resulting BOC compound, stirring is spent the night.After aqueous sodium carbonate furnishing alkalescence, use ethyl acetate extraction.Behind extract washing, dry (sodium sulfate), steam solvent under the decompression.Yield: 12%, Mp:96-100 ℃.IR ν
Max(KBr): 3359,1662,1594,1555cm
-1.NMR (CDCl
3): 2.22 (3H, s), 3.48 (2H, br.s), 3.98 (2H, m), 4.27 (2H, d, J=14.4Hz), 5.07 (1H, d, J=14.4Hz), 6.32-7.69 (17H, m). ultimate analysis (C
30H
28N
4O
30.2H
2O)
Calculated value: C, 72.62; H, 5.77; N, 11.29
Measured value: C, 72.49; H, 5.88; N, 11.49.
Embodiment 5 2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N-(2-(N '-(tolyl) urea groups) the ethyl phosphinylidyne) amino) benzophenone 5e, 5f
Use compound 4b, 4c as initial substance respectively, synthetic according to the method the same with embodiment 2.Compound 5e yield 31.2%[α]
D 24+ 14.4 (c1.151, CHCl
3) IR ν
Max(whiteruss): 3368,1741,1665,1642,1553cm
-1NMR (CDCl
3+ CD
3OD) δ: 1.0-1.5 (9H, m), 2.31 or 2.28 (add up to 3H, s), 3.65-3.80 (1H, m), 4.35-4.75 (2H, m), 6.75-7.90 (13H, m). ultimate analysis (C
30H
33N
3O
50.5H
2O)
Calculated value: C, 68.68; H, 6.53; N, 8.01
Measured value: C, 68.67; H, 6.52; N, 8.22. compound 5f[α]
D 23-18.3 (c0.717, CHCl
3).
R
8＝a：-COOCH
2Ph，
b：-COOCH
2CH＝CH
2，
c：-CH
2COOCH
2CH＝CH
2，
d：-OCH
2COOCH
2CH＝CH
2，
e：-SCH
2COOCH
2CH＝CH
2，
t：-CF
3
Embodiment 6 2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N '-(-(benzyloxy phosphinylidyne) phenyl) urea groups methyl carbon acylamino) benzophenone 7a
With the compound 6a of preparation example 7 preparations, synthetic according to the preparation method of embodiment 2 compound 5b.Mp：85-88℃。IR ν
Max(KBr): 3380,1720,1661,1597,1555cm
-1.NMR (DMSO-d
6) δ: 1.36 (9H, s), 3.53-3.85 (2H, m), 3.73 (1H, d, J=16.8Hz), 4.14 (1H, d, J=16.8Hz), 5.33 (2H, s), 6.38 (1H, br.s), 7.30-7.85 (17H, m), 8.05 (1H, br, s), 9.09 (1H, s). ultimate analysis (C
36H
25N
3O
7)
Calculated value: C, 69.55; H, 5.67; N, 6.76
Measured value: C, 69.41; H, 5.74; N, 6.79.
Embodiment 7 2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N '-(-(allyl oxygen phosphinylidyne) phenyl) urea groups methyl carbon acylamino) benzophenone 7b
With compound 6b as initial substance, according to the method synthesising title compound of embodiment 2.Mp：105-107℃。IR ν
Max(KBr): 3385,1743,1722,1662,1597,1558cm
-1.NMR (CDCl
3) δ: 1.39 (9H, s), 3.65 (1H, d, J=17.2Hz), 3.80 (1H, dd, J=17.2,4.6Hz), 4.63 (1H, d, J=17.2Hz), 4.79 (2H, d, J=5.8Hz), 5.20-5.46 (2H, m), 5.82-6.14 (2H, m), 7.01 (1H, s), 7.22-7.86 (12H, m), 7.96 (1H, br.s). ultimate analysis (C
32H
33N
3O
7)
Calculated value: C, 67.24; H, 5.82; N, 7.35
Measured value: C, 66.98; H, 5.80; N, 7.31.
Embodiment 8 2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N '-(-(2-propenyl oxygen phosphinylidyne methyl) phenyl) urea groups methyl carbon acylamino) benzophenone 7c
With compound 6c as initial substance, according to the method synthesising title compound of embodiment 2.Mp：122-124℃。IR ν max (KBr): 3360,1740,1662,1645,1610,1595,1560cm
-1.NMR (CDCl
3) δ: 1.40 (9H, s), 3.59 (2H, s), 3.64 (1H, d, J=17.2Hz), 3.77 (1H, dd, J=17.0,5.0Hz), 4.00 (1H, dd, J=17.0,5.0Hz), 4.53-4.61 (2H, m), 4.64 (1H, d, J=17.2Hz), 5.13-5.32 (2H, m), 5.72-5.99 (2H, m), 6.75 (1H, s), 6.89-6.97 (1H, m), 7.11-7.30 (4H, m), and 7.4-7.67 (6H, m), 7.72-7.84 (3H, m). ultimate analysis (C
33H
35N
3O
7)
Calculated value: C, 67.68; H, 6.02; N, 7.18
Measured value: C, 67.68; H, 6.09; N, 7.19.
Embodiment 9 2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N '-(-(2-propenyl oxygen phosphinylidyne methoxyl group) phenyl) urea groups methyl carbon acylamino) benzophenone 7d
With compound 6d as initial substance, according to the method synthesising title compound of embodiment 2.Mp：134-136℃。IR ν
Max(KBr): 3390,1760,1739,1660,1650,1610,1560,1500cm
-1.NMR (CDCl
3) δ: 1.40 (9H, s), 3.63 (1H, d, J=17.4Hz), 3.76 (1H, dd, J=17.4,3.6Hz), 4.00 (1H, dd, J=17.4,3.6Hz), 4.62 (2H, s), 4.64 (1H, d, J=17.4Hz), 4.69 (1H, d, J=5.6Hz), 5.19-5.38 (2H, m), 5.77-6.01 (2H, m), 6.57 (1H, dd, J=7.6,2.6Hz), 6.73-6.87 (2H, m), 7.00-7.18 (2H, m), 7.37-7.68 (6H, m), 7.72-7.84 (3H, m). ultimate analysis (C
33H
35N
3O
8)
Calculated value: C, 65.88; H, 5.86; N, 6.98
Measured value: C, 65.76; H, 5.89; N, 6.92.
Embodiment 10 2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N '-(-(2-propenyl oxygen phosphinylidyne methylthio group) phenyl) urea groups methyl carbon acylamino) benzophenone 7e
With compound 6e as initial substance, according to the method synthesising title compound of embodiment 2.Mp：155-157℃。IR ν
Max(KBr): 3380,1740,1650,1595,1550cm
-1.NMR (CDCl
3) δ: 1.40 (9H, s), 3.63 (1H, d, J=17.4Hz), 3.67 (2H, s), 3.78 (1H, dd, J=17.2,5.6Hz), 4.01 (1H, dd, 17.2,5.6Hz), 4.55-4.62 (2H, m), 4.73 (1H, d, J=17.4Hz), 5.16-5.32 (2H, m), 5.73-6.00 (2H, m), 6.86 (1H, s), 6.96-7.07 (1H, m), 7.08-7.16 (2H, m), 7.33 (10H, m). ultimate analysis (C
33H
35N
3O
7S)
Calculated value: C, 64.17; H, 5.71; N, 6.80; S, 5.19
Measured value: C, 64.22; H, 5.80; N, 6.79; S, 5.08.
Embodiment 11 2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N '-(-(2-(trityl) tetrazolium-5-yl) phenyl) urea groups methyl carbon acylamino) benzophenone 7f
With compound 6f as initial substance, according to the method synthesising title compound of embodiment 2.Be Powdered.IR ν
Max(KBr): 3380,1740,1662,1595,1560,1515cm
-1.NMR (CDCl
3) δ: 1.40 (9H, s), 3.63 (1H, d, J=17.2Hz), 3.80 (1H, d, J=17.2Hz), 3.99 (1H, dd, J=17.2,4.6Hz), 4.63 (1H, d, 17.2Hz), 5.71 (1H, br.s), 6.70 (1H, s), 7.00-7.90 (28H, m). ultimate analysis (C
48H
43N
7O
50.5CH
3C
6H
5)
Calculated value: C, 73.29; H, 5.61; N, 11.62
Measured value: C, 72.95; H, 5.76; N, 11.31.
Embodiment 12 2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N '-(-(2-(trityl) tetrazolium-5-ylmethoxy) phenyl) urea groups methyl carbon acylamino) benzophenone 7g
With compound 6g as initial substance, according to the method synthesising title compound of embodiment 2.IR ν
Max(KBr): 3380,1740,1662,1600,1548cm
-1.NMR (CDCl
3) δ: 1.39 (9H, s), 3.64 (1H, d, J=17.4Hz), 3.76 (1H, dd, J=17.8,4.6Hz), 3.98 (1H, dd, J=17.8,4.6Hz), 4.64 (1H, d, 17.4Hz), 5.28 (2H, s), 5.81 (1H, br.s), 6.58-6.73 (2H, m), 6.83-6.91 (1H, m), 6.99-7.66 (23H, m), 7.71-7.83 (3H, m). ultimate analysis (C
49H
45N
7O
60.3CH
3C
6H
5)
Calculated value: C, 71.74; H, 5.58; N, 11.46
Measured value: C, 71.58; H, 5.65; N, 11.38.
Embodiment 13 2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N '-(-(trifluoromethyl) phenyl) urea groups methyl carbon acylamino) benzophenone 7t
With compound 6t as initial substance, according to the method synthesising title compound of embodiment 2.Be Powdered.NMR(CDCl
3)δ：1.36(9H，s)，3.68(1H，d，J＝17.2Hz)，3.79(1H，d，J＝17.4Hz)，4.10(1H，d，J＝17.4Hz)，4.61(1H，d，J＝17.2Hz)，7.07-7.88(13H，m).
R
8＝u：m-Cl，v：m-Br，w：m-CN，x：m-OCH
3，y：p-Cl，z：p-Me，aa：H
8ha：X＝Na，8hb：X＝1/2Ca
Embodiment 14 2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N '-(chloro-phenyl-) urea groups methyl carbon acylamino) benzophenone 7u
The acid amides 6u of preparation example 15 preparation (977mg, 2mmol), bromo-acetic acid tert-butyl (420 μ g, 2.6mmol), salt of wormwood (359mg, 2.6mmol) and potassiumiodide (33mg, dimethyl formamide 0.2mmol) (6ml) solution stirring is spent the night.After in the impouring water, the mixture ethyl acetate extraction.Behind extract washing, dry (sodium sulfate), steam solvent under the decompression.Residue toluene recrystallization.Yield 58%, Mp.160-161 ℃.IR ν
Max(KBr): 1742,1662,1644,1595,1546cm
-1.NMR (CDCl
3) δ: 1.37 (9H, s), 3.67 (1H, d, J=17.2Hz), 3.77 (1H, dd, J=17.4,5.6Hz), 4.05 (1H, dd, J=17.4,5.6Hz), 4.05 (1H, dd, J=17.2,5.6Hz), 4.60 (1H, d, J=17.2Hz), 6.12 (1H, br.s), (6.89 1H.br.s), 7.06 (1H, m), 7.25 (2H, s), 7.41-7.69 (7H, m), 7.80 (2H, m). ultimate analysis (C
28H
28N
3O
5Cl)
Calculated value: C, 64.43; H, 5.41; Cl, 6.79; N, 8.05
Measured value: C, 64.19; H, 5.54; Cl, 6.65; N, 7.93.
Embodiment 15 2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N '-(bromophenyl) urea groups methyl carbon acylamino) benzophenone 7v
With the compound 6v of preparation example 16 preparation as initial substance, according to the method synthesising title compound of embodiment 14.IR ν
Max(KBr): 1741,1663,1593,1539cm
-1.NMR (CDCl
3) δ: 1.38 (9H, s), 3.67 (1H, d, J=17.2Hz), 3.78 (1H, dd, J=17.2,4.4Hz), 4.04 (1H, dd, J=17.4,4.4Hz), 4.61 (1H, d, J=17.2Hz), 6.09 (1H, br.s), 6.95-7.27 (5H, m), 7.42-7.70 (6H, m), 7.76-7.85 (3H, m). ultimate analysis (C
28H
28N
3O
5Br)
Calculated value: C, 59.37; H, 4.98; Br, 14.11; O, 7.42
Measured value: C, 59.25; H, 4.98; Br, 13.85; N, 7.33.
Embodiment 16 2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N '-(cyano-phenyl) urea groups methyl carbon acylamino) benzophenone 7w
With the compound 6w of preparation example 17 preparation as initial substance, according to the method synthesising title compound of embodiment 14.IR ν
Max(KBr): 2228,1741,1664,1594,1553cm
-1.NMR (CDCl
3) δ: 1.36 (9H, s), 3.69 (1H, d, J=17.2Hz), 3.73 (1H, dd, J=17.2,6.0Hz), 4.12 (1H, dd, J=17.2,6.0Hz), 4.60 (1H, d, J=17.2Hz), 6.41 (1 H, br.s), 7.08-7.33 (4H, m), 7.43-7.91 (10H, m). ultimate analysis (C
29H
28N
4O
50.4H
2O)
Calculated value: C, 67.01; H, 5.58; N, 10.78
Measured value: C, 66.98; H, 5.56; N, 10.71.
Embodiment 17 2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N '-(m-methoxyphenyl) urea groups methyl carbon acylamino) benzophenone 7x
With the compound 6x of preparation example 18 preparation as initial substance, according to the method synthesising title compound of embodiment 14.Mp.153-155℃。IR ν
Max(KBr): 1743,1663,1646,1608,1556,1575cm
-1.NMR (CDCl
3) δ: 1.39 (9H, s), 3.64 (1H, d, J=17.2Hz), 3.75 (3H, s), 3.78 (1H, dd, J=17.2,4.0Hz), 4.03 (1H, dd, J=17.2,4.0Hz), 4.63 (1H, d, J=17.2Hz), 6.00 (1H, br.s), 6.51-6.58 (1H, m), 6.68-6.77 (1H.m), 6.98-7.16 (3H, m), 7.40-7.67 (6H, m), 7.40-7.67 (6H, m). ultimate analysis (C
29H
31N
3O
6)
Calculated value: C, 67.30; H, 6.04; N, 8.12
Measured value: C, 67.30; H, 6.10; N, 8.16
Embodiment 18 2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N '-(rubigan) urea groups methyl carbon acylamino) benzophenone 7y
With the compound 6y of preparation example 19 preparation as initial substance, according to the method synthesising title compound of embodiment 14.Mp.196-197℃。IR ν
Max(KBr): 1742,1660,1578,1548cm
-1.NMR (CDCl
3) δ: 1.37 (9H, s), 3.66 (1H, d, J=17.2Hz), 3.77 (1H, dd, J=17.4,4.4Hz), 4.07 (1H, dd, J=17.4,4.4Hz), 4.61 (1H, d, J=17.2Hz), 6.10 (1H, br.s), 7.06-7.28 (6H, m), 7.43-7.83 (8H, m). ultimate analysis (C
28H
28N
3O
5Cl)
Calculated value: C, 64.43; H, 5.41; Cl, 6.79; N, 8.05
Measured value: C, 64.41; H, 5.49; Cl, 6.90; N, 8.04.
Embodiment 19 2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N '-(p-methylphenyl) urea groups methyl carbon acylamino) benzophenone 7z
With the compound 6z of preparation example 20 preparation as initial substance, according to the method synthesising title compound of embodiment 14.Mp.182-183℃。IR ν
Max(KBr): 1742,1661,1598,1577,1548cm
-1.NMR (CDCl
3) δ: 1.43 (9H, s), 2.28 (3H, s), 3.64 (1H, d, J=17.2Hz), 3.74 (1H, dd, J=17.4,4.0Hz), 4.01 (1H, dd, J=17.4,4.0Hz), 4.63 (1H, d, J=17.2Hz), 5.77 (1H, br.s), 7.00-7.22 (4H, m), 7.42-7.83 (10H, m). ultimate analysis (C
29H
31N
3O
5)
Calculated value: C, 69.44; H, 6.23; N, 8.38
Measured value: C, 69.68; H, 6.33; N, 8.34.
Embodiment 20 2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N '-phenylurea ylmethyl carbon acylamino) benzophenone 7aa
With the compound 6aa of preparation example 21 preparation as initial substance, according to the method synthesising title compound of embodiment 14.Mp.166-167℃。IR ν
Max(KBr): 1743,1662,1598,1553,1498cm
-1.NMR (CDCl
3) δ: 1.39 (9H, s), 3.65 (1H, d, J=17.4Hz), 3.79 (1 H, dd, J=17.6,4.2Hz), 4.04 (1H, dd, J=17.6,4.2Hz), 4.64 (1H, d, J=17.4Hz), 5.97 (1H, br.s), 7.01 (2H, br.s), 7.16-7.30 (5H, m), 7.40-7.85 (7H, m). ultimate analysis (C
28H
29N
3O
5)
Calculated value: C, 68.98; H, 6.00; N, 8.62
Measured value: C, 68.94; H, 6.03; N, 8.62.
Embodiment 21 2-((uncle's fourth oxygen phosphinylidyne methyl)-(3-(carboxyl phenyl) urea groups methyl phosphinylidyne)) Uvinul A Plus sodium salt 8ha
1) 2-(N '-(-(2-propenyl oxygen phosphinylidyne) phenyl) urea groups methylamino formyl) benzophenone 6b
Under ice-cooled, to from-(3-propenyl oxygen) aniline (1.3g, 6.80mmol), triphosgene (665mg, 2.38mmol) and triethylamine (996 μ l, 7.14mmol) tetrahydrofuran (THF) (50ml) solution with between the preparation of the described method of EP-508796-A1-(3-propenyl oxygen phosphinylidyne) phenyl isocyanate solution in, add compound 3a (1.852g, tetrahydrofuran (THF) 5.53mmol) (10ml) solution of preparation example 3 preparations.(810 μ l, 5.80mmol), the same processing of method with preparation example 15 makes this compound (1.678g to add triethylamine again.Yield 68%).Mp.68-71℃。IR ν
Max(KBr): 3350,1718,1692,1659,1595,1580,1557,1520cm
-1.NMR (CDCl
3) δ: 4.12 (2H, d, J=5.6Hz), 4.77 (2H, d, J=5.6Hz), 5.20-5.43 (2H, m), and 5.88-6.10 (2H, m), 7.04-7.18 (3H, m), 7.36-7.70 (10H, m), 7.90 (1H, br.s), 8.54 (1H, d, J=8.6Hz). ultimate analysis (C
26H
23N
3O
5)
Calculated value: C, 68.26; H, 5.07; N, 9.19
Measured value: C, 68.30; H, 5.19; N, 9.16.
2) 2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N '-(-(2-propenyl oxygen phosphinylidyne) phenyl) urea groups methyl carbon acylamino) benzophenone 7b
, synthetic with compound 6b according to the method for embodiment 14 as initial substance.Mp.105-107℃。IR ν
Max(KBr): 3385,1743,1722,1662,1597,1558cm
-1.NMR (CDCl
3) δ: 1.39 (9H, s), 3.65 (1H, d, J=17.2Hz), 3.80 (1H, dd, J=17.2,4.6Hz), 4.63 (1H, d, J=17.2Hz), 4.79 (2H, d, J=5.8Hz), 5.20-5.46 (2H, m), 5.82-6.14 (2H, m), 7.01 (1H, s), 7.22-7.86 (12H, m), 7.96 (1H, br.s). ultimate analysis (C
32H
33N
3O
7)
Calculated value: C, 67.24; H, 5.82; N, 7.35
Measured value: C, 66.98; H, 5.80; N, 7.31.
3) 2-((uncle's fourth oxygen phosphinylidyne methyl)-(3-(carboxyl phenyl) urea groups methyl phosphinylidyne)) Uvinul A Plus 8h
Under 0 ℃ of stirring, to above-mentioned allyl ester compound 7b (820mg, 1.43mmol), four (triphenyl phosphine) palladium (41.4mg, 0.036mmol) and triphenyl phosphine (19mg, 0.072mmol) methylene dichloride (0.5ml) solution in, add tetramethyleneimine (127 μ l, methylene dichloride 1.51mmol) (0.5ml) solution.After 15 minutes, reaction solution dilutes with ethyl acetate, extracts with 15% sodium bicarbonate aqueous solution.Alkaline layer transfers to pH=2 with 5% hydrochloric acid, uses ethyl acetate extraction.Behind ethyl acetate layer washing, dry (sodium sulfate), decompression concentrates down, obtains Powdered title compound 8h (256mg, 34%).IRν
max(KBr)：3380，1665，1595，1555cm
-1.NMR(CDCl
3)δ：3.69(1H，d，J＝17.2Hz)，3.83(1H，dd，J＝17.2，4.6Hz)，4.05(1H，dd，J＝17.2，4.6Hz)，4.70(1H，d，J＝17.2Hz)，7.17-7.27(1H，br.s)，7.30-7.85(12H，m)，8.17(1H，s)，8.30-8.41(1H，m).
4) 2-((uncle's fourth oxygen phosphinylidyne methyl)-(3-(carboxyl phenyl) urea groups methyl phosphinylidyne)) Uvinul A Plus sodium salt 8ha
Compound 8h (11.266g, methyl alcohol 21.2mmol) (700ml) and water (50ml) solution with the neutralization of the 1 equivalent concentration caustic soda aqueous solution (21.2ml) after, decompression is concentrated down.In resulting residue, add water (200ml), lyophilize, obtain colourless powder shape title compound 8ha (12.49g, 100%).NMR (CD
3OD) δ: 1.42 (9H, s), 3.77 (1H, d, J=17.0Hz), 3.78 (1H, d, J=17.4Hz), 3.94 (1H, d, J=17.4Hz), 4.37 (1H, d, J=17.0Hz), 7.16-7.28 (1H, m), 7.44-7.87 (13H, m). ultimate analysis (C
29H
28N
3O
7Na2H
2O)
Calculated value: C, 59.08; H, 5.47; N, 7.13; Na, 3.90
Measured value: C, 59.19; H, 5.48; N, 7.42; Na, 3.95.
Embodiment 22 2-((uncle's fourth oxygen phosphinylidyne methyl)-(3-(carboxyl phenyl) urea groups methyl phosphinylidyne)) Uvinul A Plus calcium salt 8hb
Under agitation, (7.496g drips calcium chloride (1.411g, water 12.7mmol) (50ml) solution in water 12.7mmol) (200ml) solution to compound 8ha.Stir after 6 hours, leach colourless powder, obtain title compound 5.156g (70.2%).NMR (CD
3OD) δ: 1.41 (9H, s), 3.71 (1H, d, J=17.2Hz), 3.79 (1H, d, J=17.4Hz), 3.94 (1H, d, J=17.4Hz), 4.36 (1H, d, J=17.2Hz), 7.17-7.29 (1H, m), 7.23-7.90 (13H, m). ultimate analysis (C
58H
56N
6O
14Ca3H
2O)
Calculated value: C, 60.30; H, 5.41; N, 7.27; Ca, 3.47
Measured value: C, 60.74; H, 5.40; N, 7.46; Ca, 3.44.
R
8＝h：-COOH，
i：-CH
2COOH，
j：-OCH
2COOH，
k：-SCH
2COOH，
Embodiment 23 N-(uncle's fourth oxygen phosphinylidyne methyl)-2-(N '-(-(3-carboxyl phenyl) urea groups methyl carbon acylamino) benzophenone 8h
Under 0 ℃ of stirring, allyl ester compound 7b (820mg to embodiment 7 preparations, 1.43mmol), four (triphenyl phosphine) palladium (41.4mg, 0.036mmol) and triphenyl phosphine (19mg, 0.072mmol) methylene dichloride (0.5ml) solution in, add tetramethyleneimine (127 μ l, methylene dichloride 1.51mmol) (0.5ml) solution.After 15 minutes, reaction solution dilutes with ethyl acetate, extracts with 15% sodium bicarbonate aqueous solution.Alkaline layer transfers to pH=2 with 5% hydrochloric acid, uses ethyl acetate extraction.Ethyl acetate layer washing, the decompression of dry (sodium sulfate) back concentrate down, obtain Powdered title compound (256mg, 34%).IRν
max(KBr)：3380，1665，1595，1555cm
-1.NMR(CDCl
3)δ：3.69(1H，d，J＝17.2Hz)，3.83(1H，dd，J＝17.2，4.6Hz)，4.05(1H，dd，J＝17.2，4.6Hz)，4.70(1H，d，J＝17.2Hz)，7.17-7.27(1H，br.s)，7.30-7.85(12H，m)，8.17(1H，s)，8.30-8.41(1H，m).
Embodiment 24 2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N '-(-(carboxymethyl) phenyl) urea groups methyl carbon acylamino) benzophenone 8i
With the allyl ester compound 7c of embodiment 8 preparations, with 23 the same synthesizing of embodiment.Mp.96-98 ℃ of IR ν
Max(KBr): 3380,1739,1661,1594,1555cm
-1.NMR (CDCl
3) δ: 1.41 (9H, s), 3.57 (2H, s), 3.63 (1H, d, J=17.2Hz), 3.75 (1H, dd, J=17.0,5.0Hz), 4.02 (1H, dd, J=17.0,5.0Hz), 4.61 (1H, d, J=17.2Hz), 6.42 (1H, br.s), 6.81-6.97 (2H, m), 7.12-7.24 (1H, m), 7.40-7.70 (7H, m), 7.71-7.82 (3H, m). ultimate analysis (C
30H
31N
3O
70.4H
2O)
Calculated value: C, 65.18; H, 5.80; N, 7.6
Measured value: C, 65.15; H, 5.77; N, 7.46.
Embodiment 25 2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N '-(-(carboxymethoxyl) phenyl) urea groups methyl carbon acylamino) benzophenone 8j
With the allyl ester compound 7d of embodiment 9 preparations, with 23 the same synthesizing of embodiment.Be Powdered.IR ν
Max(KBr): 3380,1740,1662,1599,1551cm
-1.NMR (CDCl
3) δ: 1.41 (9H, s), 3.67 (1H, d, J=17.0Hz), 3.76 (1H, dd, J=17.4,3.6Hz), 4.06 (1H, dd, J=17.4,3.6Hz), 4.59 (2H, s), 4.62 (1H, d, J=17.0Hz), 6.38-6.53 (2H, m), 6.71 (1H, br.s), 7.04-7.26 (2H, m), 7.40-7.70 (6H, m), 7.73-7.82 (3H, m). ultimate analysis (C
30H
31N
3O
80.4H
2O)
Calculated value: C, 63.35; H, 5.64; N, 7.39
Measured value: C, 63.34; H, 5.70; N, 7.29.
Embodiment 26 2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N '-(-(carboxy-methyl mercapto-group) phenyl) urea groups methyl carbon acylamino) benzophenone 8k
With the allyl ester compound 7e of embodiment 10 preparations, with 23 the same synthesizing of embodiment.IR ν
Max(KBr): 3380,1738,1661,1595,1547cm
-1.NMR (CDCl
3) δ: 1.38 (9H, s), 3.60 (2H, s), 3.68 (1H, d, J=17.4Hz), 3.80 (1H, dd, J=17.2,5.6Hz), 4.03 (1H, dd, J=17.2,5.6Hz), 4.60 (1H, d, J=17.4Hz), 6.28 (1H, br.s), 6.97-7.24 (4H, m), 7.38-7.70 (7H, m), 7.76-7.88 (3H, m). ultimate analysis (C
30H
31N
3O
7S0.5H
2O)
Calculated value: C, 61.42; H, 5.50; N, 7.16; S, 5.47
Measured value: C, 61.51; H, 5.51; N, 7.04.
Embodiment 27 2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N '-(-(tetrazolium-5-yl) phenyl) urea groups methyl carbon acylamino) benzophenone 8p
(570mg adds 1N hydrochloric acid (2.9ml), in stirring at room in tetrahydrofuran (THF) 0.71mmol) (3ml) and ethanol (10ml) solution to the trityl compound 7f of embodiment 11 preparations.In reaction solution, add water after 3 hours, use ethyl acetate extraction.Steam solvent behind organic layer washing, dry (sodium sulfate), obtain title compound (187mg, 33.7%).Mp：163-175℃。IR ν
Max(KBr): 3380,1740,1661,1595,1570cm
-1.NMR (CDCl
3+ CD
3OD) δ: 1.34 (9H, s), 3.67 (1H, d, J=17.4Hz), 3.85 (1H, d, J=17.4Hz), 4.01 (1H, d, J=17.4Hz), 7.07-7.92 (13H, m). ultimate analysis (C
29H
29N
7O
5H
2O)
Calculated value: C, 60.72; H, 5.45; N, 17.09
Measured value: C, 60.86; H, 5.40; N, 16.72.
Embodiment 28 2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N '-(-(tetrazolium-5-ylmethoxy) phenyl) urea groups methyl carbon acylamino) benzophenone 8q
Trityl compound 7g with embodiment 12 preparations with embodiment 27 the same carrying out, has synthesized title compound.IR ν
Max(KBr): 3400,1741,1662,1600,1555cm
-1.NMR (CDCl
3+ CD
3OD) δ: 1.39 (9H, s), 3.64 (1H, d, J=17.4Hz), 3.81 (1H, d, J=17.4Hz), 4.58 (1H, d, J=17.4Hz), 5.28 (2H, dd, 20.1,14.0Hz), 6.36-6.47 (1H, m), 6.77-7.03 (3H, m), 7.44-8.00 (11H, m). ultimate analysis (C
30H
31N
7O
60.4H
2O) calculated value: C, 60.78; H, 5.41; N, 16.54 measured values: C, 60.87; H, 5.43; N, 16.46.
Embodiment 29 2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N '-(-(carboxymethyl sulfinyl) phenyl) urea groups methyl carbon acylamino) benzophenone 8r
Compound 8k and metachloroperbenzoic acid are handled with common method, obtain title compound.Be Powdered.NMR(CDCl
3)δ：1.43(9H，s)，3.74(1H，d，J＝17.2Hz)，3.75-3.98(4H，m)，4.37(1H，d，J＝17.2Hz)，7.27-7.86(13H，m).
R
8＝h：-COOH，
i：-CH
2COOH，
j：-OCH
2COOH，
k：-SCH
2COOH，
l：-COOMe，
m：-CH
2COOMe，
n：-OCH
2COOMe，
o：-SCH
2COOMe，
Embodiment 30 2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N '-(-(methoxycarbonyl) phenyl) urea groups methyl carbon acylamino) benzophenone 91
The carboxylic acid 8h of embodiment 23 preparations handles with the diethyl ether solution of excessive diazomethane, obtains compound 91.IR ν
Max(KBr): 3390,1740,1725,1660,1595,1556cm
-1.NMR (CDCl
3) δ: 1.38 (9H, s), 3.66 (1H, d, J=17.0Hz), 3.80 (1H, dd, J=17.6,5.6Hz), 4.04 (1H, dd, J=17.6,5.6Hz), 4.63 (1H, d, J=17.0Hz), 5.96 (1H, br.s), 7.11 (1H, s), 7.22-7.32 (1H, m), 7.42-7.69 (8H, m), 7.75-7.86 (3H, m), 7.96 (1H, br.s). ultimate analysis (C
30H
31N
3O
71.3H
2O)
Calculated value: C, 63.33; H, 5.95; N, 7.38
Measured value: C, 62.12; H, 5.51; N, 7.30.
Embodiment 31 2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N '-(-(methoxycarbonyl methyl) phenyl) urea groups methyl phosphinylidyne) amino) benzophenone 9m
Carboxylic acid 8i with embodiment 24 preparations with embodiment 30 the same carrying out, obtains title compound.Yield 42%, Mp:127-129 ℃.IR ν
Max(KBr): 3359,1740,1658,1562,1494cm
-1.NMR (CDCl
3) δ: 1.39 (3H, s), 3.55 (2H, s), 3.65 (1H, d, J=17.6Hz), 3.67 (3H, s), 3.77 (1H, d, J=18.2Hz), 4.01 (1H, d, J=17.6Hz), 4.64 (1H, d, J=17.6Hz), 5.88 (1H, br.s), 6.91 (1H, m), 7.15-7.81 (13H, m). ultimate analysis (C
31H
33N
3O
7)
Calculated value: C, 66.53; H, 5.94; N, 7.56
Measured value: C, 66.41; H, 6.02; N, 7.61.
Embodiment 32 2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N '-(-(methoxycarbonyl methoxyl group) phenyl) urea groups methyl carbon acylamino) benzophenone 9n
With the carboxylic acid 8j of embodiment 25 preparation, with synthetic the same the synthesizing of the compound 91 of embodiment 30.Mp：74-77℃。IR ν
Max(KBr): 3380,1741,1662,1599,1550cm
-1.NMR (CDCl
3) δ: 1.40 (9H, s), 3.63 (1H, d, J=17.4Hz), 3.75 (1H, dd, J=17.4,8.6Hz), 3.63 (1H, d, J=17.4Hz), 4.01 (1H, dd, J=17.4,8.6Hz), 4.60 (2H, s), 4.63 (1H, d, J=17.4Hz), 5.82 (1H, br.s), 6.57 (1H, dd, J=7.6,2.6Hz), 6.72-6.88 (2H, m), 7.00-7.18 (2H, m), and 7.37-7.68 (6H, m), 7.72-7.85 (3H, m). ultimate analysis (C
31H
33N
3O
8)
Calculated value: C, 64.69; H, 5.78; N, 7.30
Measured value: C, 64.54; H, 5.85; N, 7.21.
Embodiment 33 2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N '-(-(methoxycarbonyl methylthio group) phenyl) urea groups methyl carbon acylamino) benzophenone 9o
With the carboxylic acid 8k of embodiment 26 preparation, with synthetic the same the synthesizing of the compound 91 of embodiment 30.Mp：131-133℃。IR ν
Max(KBr): 3375,1741,1665,1653,1598,1550cm
-1.NMR (CDCl
3) δ: 1.40 (9H, s), 3.66 (1H, d, J=17.4Hz), 3.67 (2H, s), 3.72 (3H, s), 3.82 (1H, dd, J=17.2,5.6Hz), 4.05 (1H, dd, J=17.2,5.6Hz), 4.64 (1H, d, J=17.4Hz), 5.99 (1H, br.s), 6.91-7.20 (4H, m), 7.32-7.73 (7H, m), 7.75-7.87 (3H, m). ultimate analysis (C
31H
33N
3O
7S)
Calculated value: C, 62.93; H, 5.62; N, 7.10; S, 5.42
Measured value: C, 62.84; H, 5.68; N, 7.07; S, 5.26.
Embodiment 34 2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N '-(-(methoxycarbonyl methyl sulfinyl) phenyl) urea groups methyl carbon acylamino) benzophenone 9s
Use carboxylic acid 8r, with synthetic the same the synthesizing of the compound 91 of embodiment 30.Be Powdered.NMR(CDCl
3)δ：1.41(9H，s)，3.70(3H，s)，3.73(1H，d，J＝17.2Hz)，3.74-4.00(4H，m)，4.37(1H，d，J＝17.2Hz)，7.09-7.87(13H，m).
Embodiment 35 2-(N-(pyrrolidyl phosphinylidyne methyl)-N '-(-(methoxycarbonyl) phenyl) urea groups methyl carbon acylamino) benzophenone 10
Use is with the same method synthetic 6m of preparation method of the 6c that obtains with preparation example 9, according to the method synthesising title compound the same with embodiment 1.Yield 30.4%, Mp.189-194 ℃ of IR ν
Max(KBr): 3378,3332,1740,1653,1595,1561cm
-1.NMR (CDCl
3) δ: 1.84 (4H, m), 3.34 (4H, m), 3.56 (2H, s), 3.66 (3H, s), 3.82 (1H, d, J=16.8Hz), 3.86 (2H, q, J=17.2Hz), 4.82 (1H, d, J=16.8Hz), 5.84 (1H, br.s), 6.90-6.98 (1H, m), and 7.17-7.95 (13H, m). ultimate analysis (C
31H
32N
4O
6)
Calculated value: C, 66.89; H, 5.79; N, 10.07
Measured value: C, 66.66; H, 5.83; N, 10.05.
R
8=a:-CH
3B:-CF
3C:-COOCH
2CH=CH
2
d：-COOH?e：-COOCH
3
Embodiment 36 cyclohexyl-(2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N-(N '-(tolyl) urea groups methyl phosphinylidyne) amino) phenyl) ketone 15a
Compound 14a with preparation example 24 preparations with embodiment 14 the same carrying out, has prepared target compound 15a.Mp.128-130℃。IR ν
Max(KBr): 3383,1741,1673,1647,1612,1595,1557,1522cm
-1.NMR (CDCl
3) δ: 1.10-1.53 (5H, m), 1.47 (9H, s), 1.62-1.97 (5H, m), 2.27 (3H, s), 3.60 (1H, d, J=17.2Hz), 3.64 (1H, d, J=17.2Hz), 3.81 (1H, d, J=17.2Hz), 4.61 (1H, d, 17.2Hz), 6.78 (1H, m), 7.06-7.20 (4H, m), 7.54-7.73 (4H, m), 7.91 (1H, m). ultimate analysis (C
29H
37N
3O
5)
Calculated value: C, 68.62; H, 7.35; N, 8.28
Measured value: C, 68.42; H, 7.34; N, 8.32.
Embodiment 37 cyclohexyl-(2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N-(N '-(-(trifluoromethyl) phenyl) urea groups methyl phosphinylidyne) amino) phenyl) ketone 15b
Compound 14b with preparation example 25 preparations with embodiment 14 the same carrying out, has prepared the 15b of target compound.Be the amorphism solid.IR ν
Max(KBr): 3374,1741,1741,1685,1651,1597,1560,1511cm
-1.NMR (CDCl
3) δ: 1.11-1.60 (5H, m), 1.47 (9H, s), 1.63-1.96 (5H, m), 3.20 (1H, m), 3.60 (1H, d, J=17.0Hz), 3.66 (1H, d, J=18.4Hz), 3.82 (1H, d, J=18.4Hz), 4.61 (1H, d, J=17.0Hz), 7.06-7.28 (2H, m), 7.33-7.52 (2H, m), 7.56-7.76 (2H, m), 7.81 (1H, br.s), 7.88 (1H, m). ultimate analysis (C
29H
34F
3N
3O
5)
Calculated value: C, 62.02; H, 6.10; F, 10.15; N, 7.48
Measured value: C, 61.79; H, 6.08; F, 9.89; N, 7.39.
Embodiment 38 cyclohexyl-(2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N-(N '-(-(allyl oxygen phosphinylidyne) phenyl) urea groups methyl phosphinylidyne) amino) phenyl) ketone 15c
Compound 14c with preparation example 26 preparations with embodiment 14 the same carrying out, has prepared target compound 15c.Be the amorphism solid.IR ν
Max(KBr): 3374,1722,1685,1650,1594,1555cm
-1.NMR (CDCl
3) δ: 1.12-1.95 (10H, m), 1.40 (9H, s), 3.07 (1H, m), 3.53 (1H, d, J=17.2Hz), 3.73 (1H, d, J=17.4Hz), 3.93 (1H, d, J=17.4Hz), 4.77-4.82 (2H, m), 4.80 (1H, d, J=17.2Hz), 5.19-5.47 (2H, m), 5.89-6.22 (2H, m), 7.13-7.35 (3H, m), 7.48-7.78 (4H, m), 7.80 (1H, br.s). ultimate analysis (C
32H
39N
3O
70.2H
2O)
Calculated value: C, 66.12; H, 6.68; N, 7.23
Measured value: C, 66.18; H, 6.79; N, 7.17.
Embodiment 39 cyclohexyl-(2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N-(N '-(carboxyl phenyl) urea groups methyl phosphinylidyne) amino) phenyl) ketone 15d
Use compound 15c,, prepared target compound 15d with embodiment 23 the same carrying out.Mp.175-181℃。IR ν
Max(KBr): 3379,1735,1685,1610,1595,1554cm
-1.NMR (CDCl
3) δ: 1.08-1.55 (5H, m), 1.46 (9H, s), 1.61-1.98 (5H, m), 3.19 (1H, m), 3.60 (1H, d, J=17.2Hz), 3.66 (1H, d, J=17.0Hz), 3.83 (1H, d, J=17.0Hz), 4.62 (1H, d, J=17.2Hz), 7.27 (1H, t, J=6.0Hz), 7.51-7.75 (5H, m), 7.86-7.93 (2H, m). ultimate analysis (C
29H
35N
3O
71.2H
2O)
Calculated value: C, 62.29; H, 6.74; N, 7.51
Measured value: C, 62.11; H, 6.35; N, 7.37.
Embodiment 40 cyclohexyl-(2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N-(N '-(-(methoxycarbonyl) phenyl) urea groups methyl phosphinylidyne) amino) phenyl) ketone 15e
Use compound 15d,, prepared target compound 15e with embodiment 30 the same carrying out.Be the amorphism solid.IR ν
Max(KBr): 3380,1724,1664,1594,1555cm
-1.NMR (CDCl
3) δ: 1.13-1.93 (10H, m), 1.43 (9H, s), 3.07 (1H, m), 3.49 (1H, d, J=17.1Hz), 3.75 (1H, dd, J=17.1,5.1Hz), 3.88 (3H, s), 3.90 (1H, dd, J=17.1,5.1Hz), 4.80 (1H, d, J=17.1Hz), 5.87 (1H, br.s), 6.93 (1H, s), 7.43-7.84 (8H, s), 7.94 (1H, s). ultimate analysis (C
30H
37N
3O
70.2H
2O)
Calculated value: C, 64.90; H, 6.79; N, 7.57
Measured value: C, 64.95; H, 6.52; N, 7.48.
R=
26a:X=4-CF
3, 26b:X=2-F, 26c:X=4-CN,
Embodiment 41 ((2-(4-(trifluoromethyl) benzoyl) phenyl)-(2-(tolyl urea groups between 3-) acetyl) amino) tert.-butyl acetate 26a
In room temperature, to 4-(trifluoromethyl) Benzoyl chloride (53 μ l, add in toluene 0.36mmol) (4ml) solution dichloro diacetonitrile palladium (12.5mg, 0.036mmol).(200mg 0.36mmol), stirred 20 minutes at 50 ℃ to add ((2-(trimethylammonium stannyl) phenyl)-(2-(tolyl urea groups between 3-) acetyl) amino) tert.-butyl acetate (compound 25) subsequently.Interpolation dichloro diacetonitrile palladium (6.2mg, 0.018mmol), restir 10 minutes.In reaction solution, add frozen water, stirring, water layer ethyl acetate extraction 2 times.Organic layer is with the saturated common salt water washing, with concentrating behind the anhydrous magnesium sulfate drying.Residue is refining with silica gel column chromatography, obtains target compound 26a (93mg).Yield 46%.NHR(CDCl
3)δ：1.40(9H，s)，2.28(3H，s)，3.70(1H，d，J＝17.2Hz)，3.80(1H，dd，J＝4.4Hz，17.7Hz)，3.97(1H，dd，J＝4.6Hz，17.7Hz)，4.63(1H，d，J＝17.2Hz)，5.77-5.87(1H，m)，6.67(1H，brs)，6.80-7.18(4H，m)，7.41-7.94(8H，m).
Embodiment 42 ((2-(2-fluorobenzoyl) phenyl)-(2-(tolyl urea groups between 3-) acetyl) amino) tert.-butyl acetate 26b
With ((2-(trimethylammonium stannyl) phenyl)-(2-(tolyl urea groups between 3-) acetyl) amino) tert.-butyl acetate (compound 25) (200mg) and 2-fluorobenzoyl chloride (43 μ l), according to the synthesis method synthesising title compound 26b (56mg) of compound 26a.Yield 30%.NHR(CDCl
3)δ：1.41(9H，s)，2.28(3H，s)，3.68(1H，d，J＝17.6Hz)，3.81(1H，dd，J＝4.2Hz，17.5Hz)，4.01(1H，dd，J＝4.6Hz，17.5Hz)，4.67(1H，d，J＝17.6Hz)，5.82-5.95(1H，m)，5.98-7.75(13H，m).
Embodiment 43 ((2-(4-cyano group benzoyl) phenyl)-(2-(tolyl urea groups between 3-) acetyl) amino) tert.-butyl acetate 26c
With ((2-(trimethylammonium stannyl) phenyl)-(2-(tolyl urea groups between 3-) acetyl) amino) tert.-butyl acetate (compound 25) (200mg) and 4-cyano-benzoyl chloride (59mg), according to the synthesis method of compound 26a, synthesising title compound 26c (88mg).Yield 47%.
1H?NHR(CDCl
3)δppm：1.39(9H，s)，2.29(3H，s)，3.74(1H，d，J＝17.2Hz)，3.80(1H，dd，J＝4.6Hz，17.6Hz)，3.93(1H，dd，J＝4.2Hz，17.6Hz)，4.60(1H，d，J＝17.2Hz)，5.82-5.89(1H，m)，6.73-7.20(5H，m)，7.42-7.94(8H，m).
Embodiment 44 ((2-(diamantane-1-phosphinylidyne) phenyl)-(2-(tolyl urea groups between 3-) acetyl) amino) tert.-butyl acetate 26d
With ((2-(trimethylammonium stannyl) phenyl)-(2-(tolyl urea groups between 3-) acetyl) amino) tert.-butyl acetate (compound 25) (250mg) and diamantane-1-carbonyl chloride (89mg), according to the synthesis method of compound 26a, synthesized title compound 26d (40mg).Yield 16%.
1H?NHR(CDCl
3)δppm：1.43(9H，s)，1.71(6H，s)，1.90(6H，s)，2.05(3H，s)，2.30(3H，s)，3.69(1H，d，J＝17.2Hz)，3.90(1H，d，J＝17.4Hz)，4.01(1H，d，17.4Hz)，4.63(1H，d，J＝17.2Hz)，5.83(1H，brs)，6.74-7.46(9H，m).
Embodiment 45 ((2-(1-oxo-2-propyl group amyl group)-(2 (tolyl urea groups between 3-) acetyl) amino) tert.-butyl acetate 26e
With ((2-(trimethylammonium stannyl) phenyl)-(2-(tolyl urea groups between 3-) acetyl) amino) tert.-butyl acetate (compound 25) (42mg) and 2-n-propyl n-amyl chloride (12mg), according to the synthesis method of compound 26a, synthesized title compound 26e (7mg).Yield 18%.NHR(CDCl
3)δ：0.85-0.91(6H，m)，1.42(9H，s)，2.30(3H，s)，3.49(1H，d，J＝17.4Hz)，3.65(1H，d，17.4Hz)，3.92(1H，d，17.4Hz)，4.84(1H，d，J＝17.4Hz)，5.97(1H，brs)，6.80-7.18(5H，m)，7.38-7.78(4H，m).
Embodiment 46 ((2-(cyclopropane phosphinylidyne) phenyl)-(2-(tolyl urea groups between 3-) acetyl) amino) tert.-butyl acetate 26f
With ((2-(trimethylammonium stannyl) phenyl)-(2-(tolyl urea groups between 3-) acetyl) amino) tert.-butyl acetate (compound 25) (112mg) and cyclopropane carbonyl chloride (18.1 μ l), according to the synthesis method of compound 26a, synthesized title compound 26f (45mg).Yield 48%.NHR(CDCl
3)δ：1.02-1.14(2H，m)，1.19-1.31(2H，m)，1.41(9H，s)，2.28(3H，s)，2.38-2.47(1H，m)，3.56(1H，d，J＝17.4Hz)，3.76(1H，dd，J＝5.0Hz，17.5Hz)，3.90(1H，dd，J＝4.6Hz，17.5Hz)，4.82(1H，d，J＝17.4Hz)，5.98-6.07(1H，m)，6.82(1H，d，J＝7.0Hz)，6.99-7.21(4H，m)，7.39-7.70(3H，m)，7.81-7.88(1H，m).
Embodiment 47 ((2-(trans-4-methylcyclohexane-1-phosphinylidyne) phenyl)-(2-(tolyl urea groups between 3-) acetyl) amino) tert.-butyl acetate 26g
With (112mg) and the synthetic acyl chlorides of thionyl chloride (120 μ l) and trans-4-methylcyclohexane-1-carboxylic acid (29mg) from ((2-(trimethylammonium stannyl) phenyl)-(2-(tolyl urea groups between 3-) acetyl) amino) tert.-butyl acetate (compound 25), according to the synthesis method of compound 26a, synthesized title compound 26g (35mg).Yield 34%.NHR(CDCl
3)δ：0.84-1.93(9H，m)，0.90(3H，d，J＝6.4Hz)，1.43(9H，s)，2.30(3H，s)，2.90-3.07(1H，m)，3.48(1H，d，J＝17.2Hz)，3.68(1H，dd，J＝4.6Hz，17.7Hz)，3.89(1H，dd，J＝4.6Hz，17.7Hz)，4.80(1H，d，J＝17.2Hz)，5.85-5.99(1H，m)，6.74(1H，s)，6.85(1H，d，J＝6.8Hz)，7.02-7.32(3H，m)，7.47-7.76(4H，m).
Embodiment 48 ((2-(N-(benzyloxy phosphinylidyne) piperidines-4-phosphinylidyne) phenyl)-(2-(tolyl urea groups between 3-) acetyl) amino) tert.-butyl acetate 26h
With (420mg) and thionyl chloride (220 μ l) and N-(benzyloxy phosphinylidyne) piperidines-4-carboxylic acid (198mg) (J.Med.Chem. from ((2-(trimethylammonium stannyl) phenyl)-(2-(tolyl urea groups between 3-) acetyl) amino) tert.-butyl acetate (compound 25), 1988,31, the compound of 613-617 record) synthetic acyl chlorides, according to the synthesis method of compound 26a, synthesized title compound 26h (232mg).Yield 48%.NHR(CDCl
3)δ：1.41(9H，s)，1.50-1.92(4H，m)，2.28(3H，s)，2.77-3.02(2H，m)，3.16-3.36(1H，m)，3.50(1H，d，J＝17.2Hz)，3.72(1H，dd，J＝4.6Hz，17.6Hz)，3.85(1H，dd，J＝4.2Hz，17.6Hz)，4.04-4.34(2H，m)，4.75(1H，d，J＝17.2Hz)，5.86-5.97(1H，m)，6.77-7.20(5H，m)，7.48-7.73(4H，m).
Embodiment 49 ((2-(piperidines-4-phosphinylidyne) phenyl)-(2-(tolyl urea groups between 3-) acetyl) amino) tert.-butyl acetate 60
((2-(N-(benzyloxy phosphinylidyne) piperidines-4-phosphinylidyne) phenyl)-(2-(tolyl urea groups between 3-) acetyl) amino) tert.-butyl acetate (compound 26g) (9.7mg, 0.015mmol) be dissolved in the ethanol, add palladium hydroxide-powdered carbon (2mg), under nitrogen atmosphere (1atm), stirring at room 24 hours.Reacting liquid filtering, filtrate decompression concentrate.Residue is refining with silica gel column chromatography, obtains target compound 60 (6.0mg).Yield 79%.NHR(CDCl
3)δ：1.42(9H，s)，1.53-1.76(2H，m)，1.76-1.92(2H，m)，2.29(3H，s)，2.60-2.82(2H，m)，3.08-3.28(3H，m)，3.52(1H，d，J＝17.2Hz)，3.63-3.76(1H，m)，3.79-3.94(1H，m)，4.77(1H，d，J＝17.2Hz)，5.99(1H，brs)，6.83(1H，d，J＝6.6Hz)，7.02-7.19(4H，m)，7.46-7.77(4H，m)
R
4＝
a：X＝2-F，b：X＝4-CF
3，c：X＝4-CN，
Embodiment 50 3-(3-(uncle's fourth oxygen phosphinylidyne methyl (2-(2-fluorobenzoyl) phenyl amino formyl methyl) urea groups) phenylformic acid allyl ester 31a
With compound 30a (350mg) is raw material, according to the preparation method of compound 24, has synthesized title compound 31a (230mg).Yield 65%.NHR(CDCl
3)δ：1.38(9H，s)，3.72(1H，d，J＝17.6Hz)，3.85(1H，dd，J＝4.4Hz，17.4Hz)，4.04(1H，dd，J＝5.2Hz，17.4Hz)，4.65(1H，d，J＝17.6Hz)，4.78(2H，d，J＝5.4Hz)，5.20-5.46(2H，m)，5.91-6.12(2H，m)，7.05-8.02(13H，m).
Embodiment 51 3-(3-(uncle's fourth oxygen phosphinylidyne methyl (2-(4-(trifluoromethyl) benzoyl) phenyl amino formyl methyl) urea groups) phenylformic acid allyl ester 31b
With compound 30b (300mg) is raw material, according to the preparation method of compound 24, has synthesized the compound 31b (238mg) of title.Yield 56%.NHR(CDCl
3)δ：1.36(9H，s)，3.75(1H，d，J＝17.2Hz)，3.79(1H，dd，J＝4.8Hz，17.6Hz)，4.00(1H，dd，J＝4.8Hz，17.6Hz)，4.61(1H，d，J＝17.2Hz)，4.78(2H，d，J＝5.4Hz)，5.20-5.44(2H，m)，5.90-6.12(2H，m)，7.18-7.96(13H，m).
Embodiment 52 3-(3-(uncle's fourth oxygen phosphinylidyne methyl (2-(4-cyano group benzoyl) phenyl amino formyl methyl) urea groups) phenylformic acid allyl ester 31c
With compound 30c (390mg) is raw material, according to the preparation method of compound 24, has synthesized title compound 31c (270mg), yield 53%.NHR(CDCl
3)δ：1.36(9H，s)，3.80(1H，d，J＝17.2Hz)，3.83(1H，dd，J＝4.8Hz，17.6Hz)，3.96(1H，dd，J＝4.8Hz，17.6Hz)，4.58(1H，d，J＝17.2Hz)，4.79(2H，d，J＝5.6Hz)，5.21-5.44(2H，m)，5.91-6.12(2H，m)，7.17-7.94(13H，m).
Embodiment 53 3-(3-(uncle's fourth oxygen phosphinylidyne methyl (2-(diamantane-1-phosphinylidyne) phenyl amino formyl methyl) urea groups) phenylformic acid allyl ester 31d
With compound 30d (44mg) is raw material, according to the preparation method of compound 24, has synthesized title compound 31d (30mg).Yield 56%.NHR(CDCl
3)δ：1.41(9H，s)，1.70(6H，s)，1.92(6H，s)，2.05(3H，s)，3.73(1H，d，J＝17.2Hz)，3.93(1H，dd，J＝4.4Hz，17.5Hz)，4.07(1H，dd，J＝4.8Hz，17.5Hz)，4.63(1H，d，J＝17.2Hz)，4.79(2H，d，J＝5.6Hz)，5.22-5.46(2H，m)，5.91-6.13(2H，m)，7.22-8.02(9H，m).
Embodiment 54 3-(3-(uncle's fourth oxygen phosphinylidyne methyl (2-(1-oxo-2-propyl group amyl group) phenyl amino formyl methyl) urea groups) phenylformic acid allyl ester 31e
With compound 30e (200mg) is raw material, according to the preparation method of compound 24, has synthesized title compound 31e (14mg).Yield 6%.NHR(CDCl
3)δ：0.89(6H，t，J＝7.0Hz)，1.20-1.78(8H，m)，1.41(9H，s)，3.18-3.31(1H，m)，3.51(1H，d，J＝17.2Hz)，3.68(1H，dd，J＝4.6Hz，17.6Hz)，3.95(1H，dd，J＝4.6Hz，17.6Hz)，4.79(1H，d，J＝5.6Hz)，4.83(2H，d，J＝17.2Hz)，5.22-5.45(2H，m)，5.91-6.13(2H，m)，7.10-8.00(9H，m).
Embodiment 55 3-(3-(uncle's fourth oxygen phosphinylidyne methyl (2-(2-fluorobenzoyl) phenyl amino formyl methyl) urea groups) phenylformic acid 32a
With compound 31a (60mg) is raw material, according to the method for embodiment 21 (3), has synthesized title compound 32a (40mg).Yield 71%.NHR(CDCl
3)δ：1.48(9H，s)，3.70(1H，d，J＝17.0Hz)，3.89(1H，dd，J＝3.2Hz，18.1Hz)，4.05(1H，dd，J＝3.2Hz，18.1Hz)，4.74(1H，d，J＝17.0Hz)，7.05-7.80(13H，m)，8.20(1H，s)，8.34-8.43(1H，m).
Embodiment 56 3-(3-(uncle's fourth oxygen phosphinylidyne methyl (2-(4-(trifluoromethyl) benzoyl) phenyl amino formyl methyl) urea groups) phenylformic acid 32b
With compound 31b (130mg) is raw material, according to the method for embodiment 21 (3), has synthesized title compound 32b (24mg).Yield 20%NHR (CDCl
3) δ: 1.46 (9H, s), 3.73 (1H, d, J=17.2Hz), 3.84 (1H, dd, J=3.8Hz, 18.8Hz), 3.94 (1H, dd, J=3.8Hz, 18.8Hz), 4.70 (1H, d, J=17.2Hz), 7.17 (1H, brs), and 7.29-7.98 (11H, m), 8.14 (1H, s), 8.28 (1H, d, J=7.6).
Embodiment 57 3-(3-(uncle's fourth oxygen phosphinylidyne methyl (2-(4-cyano group benzoyl) phenyl amino formyl methyl) urea groups) phenylformic acid 32c
With compound 31c (200mg) is raw material, according to the method for embodiment 21 (3), has synthesized title compound 32c (133mg).Yield 71%.NHR(CDCl
3)δ：1.47(9H，s)，3.76(1H，d，J＝17.2Hz)，3.83(1H，dd，J＝4.0Hz，17.6Hz)，3.94(1H，dd，J＝4.0Hz，17.6Hz)，4.68(1H，d，J＝17.2Hz)，7.16(1H，brs)，7.31-7.94(m，11H)，8.15(1H，s)，8.26-8.34(1H，m).
Embodiment 58 3-(3 (uncle's fourth oxygen phosphinylidyne methyl (2-(diamantane-1-phosphinylidyne) phenyl amino formyl methyl) urea groups) phenylformic acid 32d
With compound 31d (30mg) is raw material, according to the method for embodiment 21 (3), has synthesized title compound 32d (17mg).Yield 61%.NHR(CDCl
3)δ：1.49(9H，s)，1.68(6H，s)，1.90(6H，s)，2.05(3H，s)，3.73(1H，d，J＝17.2Hz)，3.96(1H，dd，J＝3.6Hz，18.4Hz)，4.10(1H，dd，J＝3.6Hz，18.4Hz)，4.65(1H，d，J＝17.2Hz)，7.19(1H，brs)，7.30-7.78(8H，m)，8.15(1H，s)，8.34-8.41(1H，m).
Embodiment 59 3-(3-(uncle's fourth oxygen phosphinylidyne methyl (2-(1-oxo-2-propyl group amyl group) phenyl amino formyl methyl) urea groups) phenylformic acid 32e
With compound 31e (14mg) is raw material, according to the method for embodiment 21 (3), has synthesized title compound 32e (7mg).Yield 54%.NHR(CDCl
3)δ：0.90(6H，t，J＝7.0Hz)，1.1?8-1.76(8H，m)，1.49(9H，s)，3.18-3.34(1H，m)，3.53(1H，d，J＝17.2Hz)，3.73(1H，dd，J＝3.6Hz，18.2Hz)，3.96(1H，dd，J＝4.6Hz，17.6Hz)，4.85(1H，d，J＝17.2Hz)，7.20-7.86(7H，m)，8.23(1H，s)，8.57(1H，d，J＝7.8).
a：R
8＝Meb：R
8＝CO
2CH
2CH＝CH
2 
Embodiment 60 ((2-(thiazole-2-phosphinylidyne) phenyl)-(2-(tolyl urea groups between 3-) acetyl) amino) tert.-butyl acetate 37a
Use compound 36a,, synthesized title compound 37a according to the synthesis method of compound 24.Mp:116 ℃ of IR ν
Max(KBr): 3347,1745,1645,1614,1563cm
-1.NMR (CDCl
3) δ: 1.43 (9H, s), 2.31 (3H, s), 3.70 (1H, d, J=17.1Hz), 4.74 (1H, d, J=17.1Hz), 3.75 (1H, d, J=17.4Hz), 4.00 (1H, d, J=17.4Hz), 5.80 (1H, brs), 6.67 (1H, m), 6.87 (1H, m), 7.01 (1H, m), 7.10-7.22 (3H, m), and 7.50-7.70 (4H, m), 7.75-7.80 (2H, m). ultimate analysis (C
27H
29N
3O
5S)
Calculated value: C, 63.89; H, 5.76; N, 8.28; S, 6.32
Measured value: C, 64.01; H, 5.88; N, 8.25; S, 6.51.
Embodiment 61 3-(3-(uncle's fourth oxygen phosphinylidyne methyl (2-(thiophene-2-phosphinylidyne) phenyl amino formyl methyl) urea groups) phenylformic acid allyl ester 37b
Use compound 36b,, synthesized title compound 37b according to the synthesis method of compound 24.Mp.142℃。IR ν
Max(KBr): 3343,1742,1722,1645,1595,1561cm
-1.NMR (CDCl
3) δ: 1.40 (9H, s), 3.69 (1H, d, J=17.5Hz), 4.71 (1H, d, J=17.5Hz), 3.78 (1H, d, J=17.5Hz), 4.00 (1H, d, J=17.5Hz), 4.80 (2H, dt, J=6.0Hz, 0.8Hz), 5.26 (1H, dd, J=9.0Hz, 1.5Hz), 5.39 (1H, dd, J=17.4Hz, 1.8Hz), 5.80-6.08 (2H, m), 7.02 (1H, s), 7.15 (1H, m), 7.31 (1H, m), 7.50-7.70 (6H, m), 7.78 (2H, m), 7.93 (1H, m). ultimate analysis (C
30H
31N
3O
7S)
Calculated value: C, 62.38; H, 5.41; N, 7.27; S, 5.55
Measured value: C, 62.19; H, 5.43; N, 7.26; S, 5.53.
Embodiment 62 3-(3-(uncle's fourth oxygen phosphinylidyne methyl (2-(thiophene-2-phosphinylidyne) phenyl amino formyl methyl) urea groups) phenylformic acid 38
With compound 37b is raw material, according to the method for embodiment 21 (3), has synthesized title compound 38.Mp：184-186℃。IR ν
Max(KBr): 3385,1735,1698,1648,1560cm
-1.NMR (DMSO-d
6) δ: 1.38 (9H, s), 3.58 (1H, dd, J=16.8Hz, 4.2Hz), 3.78 (1H, dd, J=16.8Hz, 4.2Hz), 3.72 (1H, d, J=17.2Hz), 4.29 (1H, d, J=17.2Hz), 6.37 (1H, t, J=4.4Hz), 7.20-7.35 (2H, m), 7.40-7.80 (7H, m), 7.99 (1H, m), 8.18 (1H, dd, J=5.0Hz, 1.2Hz), 8.99 (1H, s). ultimate analysis (C
27H
27N
3O
7S0.2H
2O)
Calculated value: C, 59.92; H, 5.10; N, 7.76; S, 5.92
Measured value: C, 59.87; H, 5.17; N, 7.66; S, 5.87.
A:R
8=m-Meb:R
8=p-CO
2CH
2CH=CH
2 
Embodiment 63 ((2-(4-methoxybenzoyl) phenyl)-(2-(tolyl urea groups between 3-) acetyl) amino) tert.-butyl acetate 43a
Use compound 42a,, synthesized title compound according to the synthesis method of compound 24.Mp：228-230℃。IR ν
Max(KBr): 3330,1744,1670,1640,1600cm
-1.NMR (DMSO-d
6) δ: 1.36 (9H, s), 2.22 (3H, s), 3.62 (1H, dd, J=18Hz, 5.1Hz), 3.68 (1H, d, J=16.8Hz), 3.77 (1H, dd, J=18.0Hz, 5.1Hz), 3.83 (3H, s), 4.20 (1H, d, J=16.8Hz), 6.36 (1H, t, J=5.1Hz), 6.70 (1H, d, J=7.5Hz), 7.05-7.18 (5H, m), 7.52-7.76 (5H, m), 8.79 (1H, s). ultimate analysis (C
30H
33N
3O
6)
Calculated value: C, 67.78; H, 6.25; N, 7.90
Measured value: C, 67.75; H, 6.35; N, 7.98.
Embodiment 64 3-(3-(uncle's fourth oxygen phosphinylidyne methyl (2-(4-methoxybenzoyl) phenyl) carbamoyl methyl) urea groups) phenylformic acid allyl ester 43b
Use compound 42b,, synthesized title compound according to the synthesis method of compound 24.Mp：190-191℃。IR ν
Max(KBr): 1741,1721,1645,1599,1566cm
-1.NMR (DMSO-d
6) δ: 1.38 (9H, s), 3.60-3.85 (3H, m), 3.84 (3H, s), 4.20 (1H, d, J=16.8Hz), 4.79 (2H, d, J=5.4Hz), 5.27 (1H, d, J=7.5Hz), 5.39 (1H, d, J=17.1Hz), 5.98-6.11 (1H, m), 6.38 (1H, t, J=4.5Hz), 7.08 (2H, d, J=9.0Hz), 7.37 (1H, t, J=8.0Hz), 7.49-7.76 (8H, m), 8.10 (1H, s), 9.07 (1H, s). ultimate analysis (C
33H
35N
3O
8)
Calculated value: C, 65.88; H, 5.86; N, 6.98
Measured value: C, 65.70; H, 5.91; N, 6.97.
Embodiment 65 3-(3-(uncle's fourth oxygen phosphinylidyne methyl (2-(4-methoxybenzoyl) phenyl) carbamoyl methyl) urea groups) phenylformic acid 44
With compound 43b is raw material, according to the method for embodiment 21 (3), has synthesized title compound 44.Mp：198-200℃。IR ν
Max(KBr): 1743,1694,1647,1599,1557cm
-1.NMR (CD
3OD) δ: 1.43 (9H, s), 3.69 (1H, d, J=17.2Hz), 3.79 (1H, d, J=17.4Hz), 3.85 (3H, s), 3.94 (1H, d, J=17.2Hz), 4.39 (1H, d, J=17.2Hz), 7.02-7.05 (2H, m), 7.28-7.36 (1H, m), 7.49-7.83 (8H, m), 7.97-7.99 (1H, m). ultimate analysis (C
30H
31N
3O
8)
Calculated value: C, 64.16; H, 5.56; N, 7.48
Measured value: C, 63.76; H, 5.63; N, 7.35.
Embodiment 66 3-(3-(uncle's fourth oxygen phosphinylidyne methyl (2-(N-(benzyloxy phosphinylidyne) piperidines-4-phosphinylidyne) phenyl amino formyl methyl) urea groups) phenylformic acid allyl ester 52
With 3-(3-(2-(N-(benzyloxy phosphinylidyne) piperidines-4-phosphinylidyne) phenyl amino formyl methyl) urea groups) phenylformic acid allyl ester compound 51 (599mg) is raw material, according to the synthesis method of compound 24, and synthesising title compound 52 (140mg).Yield 20%.NHR(CDCl
3)δ：1.47-1.74(2H，m)，1.74-1.94(2H，m)，1.39(9H，s)，2.76-3.04(2H，m)，3.17-3.37(1H，m)，3.53(1H，d，J＝17.6Hz)，3.62(1H，dd，J＝4.4Hz，17.5Hz)，3.88(1H，dd，J＝4.8Hz，17.5Hz)，4.05-4.33(2H，m)，4.74(1H，d，J＝17.6Hz)，4.77(2H，d，J＝4.2Hz)，5.12(2H，s)，5.22-5.44(2H，m)，5.90-6.17(2H，m)，7.20-7.41(7H，m)，7.47-7.76(6H，m)，7.93(1H，s).
Embodiment 67 3-(3-(uncle's fourth oxygen phosphinylidyne methyl (2-(N-(benzyloxy phosphinylidyne) piperidines-4-phosphinylidyne) phenyl amino formyl methyl) urea groups) phenylformic acid 53
(3-(uncle's fourth oxygen phosphinylidyne methyl (2-(N-(benzyloxy phosphinylidyne) piperidines-4-phosphinylidyne) phenyl amino formyl methyl) urea groups) phenylformic acid allyl ester compound 52 (130mg) is a raw material with 3-, according to the method for embodiment 21 (3), synthesising title compound 53 (96mg).Yield 78%.NHR(CDCl
3)δ：1.47(9H，s)，1.51-1.95(4H，m)，2.80-3.08(2H，m)，3.20-3.44(1H，m)，3.54(1H，d，J＝17.2Hz)，3.69-3.98(2H，m)，4.18-4.38(2H，m)，4.79(1H，d，J＝17.2Hz)，5.11(2H，s)，7.16(1H，brs)，7.40-7.87(8H，m)，8.21-8.40(2H，m).
Embodiment 68 3-(3-(uncle's fourth oxygen phosphinylidyne methyl (2-(piperidines-4-phosphinylidyne) phenyl amino formyl methyl) urea groups) phenylformic acid 54
To 3-(3-(uncle's fourth oxygen phosphinylidyne methyl (2-(N-(benzyloxy phosphinylidyne) piperidines-4-phosphinylidyne) phenyl amino formyl methyl) urea groups) phenylformic acid (compound 53) (19mg, 1.49 add tetrahydrobenzene (144 μ l) in ethanol μ mol) (1.0ml) solution, 10% charcoal carries palladium (15mg), reflux and stirred 30 minutes.Reacting liquid filtering, filtrate decompression are concentrated, obtain target compound 54 (12mg).Yield 79%.NHR(CD
3OD)δ：1.44(9H，s)，1.65-2.19(4H，m)，3.17-3.91(5H，m)，3.64(1H，d，J＝17.2Hz)，3.68(1H，d，J＝17.2Hz)，3.84(1H，d，J＝17.2Hz)，4.65(1H，d，J＝17.2Hz)，7.12-7.84(7H，m)，8.17(1H，m).
Embodiment 69 2-(N-(tertiary butyl carbamoyl methyl)-N '-(-(allyl oxygen carbamyl) phenyl) urea groups methyl carbon acylamino) benzophenone 16a
As initial substance,, synthesized title compound with compound 6b according to the method for embodiment 14.Be Powdered.IR ν
Max(KBr): 3372,3068,2969,2931,1719,1662cm
-1.NMR (CDCl
3) δ: 1.20 (7H, s), 1.36 (2H, s), 3.76 (1H, d, J=15.6Hz), 3.84 (1H, dd, J=4.8Hz, 17.4Hz), 3.97 (1H, dd, 1H, J=4.8Hz, 17.1Hz), 4.32 (1H, d, J=15.6Hz), 4.78 (1H, J=3.8Hz), 7.42-7.80 (12H, m), 7.95 (1H, t, J=1.8Hz). ultimate analysis (C
32H
34N
4O
60.2C
6H
140.1H
2O)
Calculated value: C, 67.44; H, 6.31; N, 9.47
Measured value: C, 67.19; H, 6.55; N, 9.59.
Embodiment 70 2-(N-(tertiary butyl carbamoyl methyl)-N '-(carboxyl phenyl) urea groups methyl carbon acylamino) benzophenone 16b
With compound 16a as initial substance, with 23 the same synthesizing of embodiment.Be Powdered.IR ν
Max(KBr): 3376,3067,2969,1661cm
-1.NMR (CDCl
3+ CD
3OD): 1.24 (9H, s), 3.76 (1H, d, J=15.6Hz), 3.80 (1H, d, J=17.4Hz), 3.99 (1H, d, J=17.4Hz), 4.40 (1H, d, J=15.6Hz), 7.30-7.89 (13H, m). ultimate analysis (C
29H
30N
4O
60.1C
6H
140.25C
4H
100.4H
2O)
Calculated value: C, 65.06; H, 6.19; N, 9.92
Measured value: C, 64.92; H, 6.48; N, 10.22.
Tested the tert-Amyloxycarbonyltetragastrin pharmacological action of the compound (I) of embodiment preparation with isolated test and live test.
Experimental example 1 usefulness Schild method is carried out sour secretion inhibition evaluation
24 hours male Sprague Dawley strain rat of fasting (freely taking the photograph water) (8 age in week) carries out urethane (urethanum) anesthesia (1.5g/kg, subcutaneous), trachea cannula is installed to guarantee breathing.After opening abdomen, per os inserts esophageal intubation until preceding stomach, near the ligation spray door, simultaneously with an intubate that is used to reclaim perfusate in duodenum insertion stomach, near and ligation pylorus.In addition, install to an administrable conduit in the duodenum, ligation.After closing abdomen, by esophageal intubation perfusion normal saline solution (heating) in stomach to 37 ℃, perfusate of collection in per 15 minutes.Perfusate is calculated acidity with the titration of 0.01N NaOH solution.Reach when stablize in acid basis secretion, continue to inject Peptavlon (10 μ g/kg/h) through total jugular vein, after 90 minutes (acid is secreted when roughly reaching maximum value) with tested compound (0.5%M.C. suspension) through conduit to intraduodenal administration.Then, the sour secretory volume of observing in per 15 minutes in a time 90 minutes changes.Inhibiting rate by the tested compound of following calculating.
The results are summarized in the following table 1.
The compounds of this invention is compared with YM-022, demonstrates sufficient effect separation property between tert-Amyloxycarbonyltetragastrin and CCK-B acceptor and CCK-A acceptor, even and effect aspect in vivo also demonstrate significant difference.
The isolated test of the antagonistic action of 2 pairs of tert-Amyloxycarbonyltetragastrin of experimental example and CCK
Investigated the pharmacological effect of the compound of the foregoing description preparation with isolated test, carry out three tests altogether:, test its antagonistic action with thick membrane sample of pallium (CCK-B acceptor) and the thick membrane sample of pancreas (CCK-A) of mouse with its antagonistic action of cavy fundic gland cell tests to gastrin receptor.
Laboratory animal: male Hartley strain cavy (body weight 450～600g), or male ddY mouse (body weight 24～30g).
(1) gastrin receptor antagonistic action
The fundic gland cell preparation:
(body weight 450～600g) bloodletting are taken out stomach after slaughtering to male Hartley strain cavy immediately, with collagenase Processing of Preparation fundic gland cell.
By the preparation of test compound and displacement test
To by the test compound dissolution in DMSO solution, make 1mM concentration.Use 50%DMSO solution stepwise dilution then, being made into respectively is the series of samples of 1/10 concentration.
To respectively contain (
125I) different concns of mark tert-Amyloxycarbonyltetragastrin (ultimate density 0.2nM) is tested and is added the fundic gland cell in the compound, so that the reaction beginning.,, draw and remove supernatant liquor after 30 minutes 25 ℃ of cultivations with 2000rpm centrifugation 5 minutes.Add ice-cooled cultivation damping fluid, centrifugation immediately after mixing is gently drawn and is removed supernatant liquor.Measure radioactivity with gamma-ray counter.In kind carry out, replace by test compound determination contrast total binding number, and measure the non-specific binding number with human body tert-Amyloxycarbonyltetragastrin I (ultimate density 2 μ M) with 50%DMSO solution.
IC
50Calculating:
Calculate the ratio (%) that is combined number (total binding number (cpm)-non-specific binding number (cpm)) by the specificity of test compound in conjunction with number (total binding number (cpm)-non-specific binding number (cpm)) with the specificity of control group, draw semilogarithmic plot, the concentration corresponding to 50% is IC
50
(2) CCK-A and CCK-B receptor antagonism
The preparation of cck receptor sample:
(body weight 24～30g) broken ends are won pallium (CCK-B) and pancreas (CCK-A) rapidly after slaughtering to male ddY mouse, add 50mM Tris hydrochloride buffer agent (pH=7.4), make thick membrane sample with teflon-glass homogenizer and Polytron homogenizer.
By the preparation of test compound and displacement test
To by the test compound dissolution in DMSO solution, be made into 1mM concentration.Use the 50%DMSO stepwise dilution then, being made into respectively is the series of samples of 1/10 concentration.
To respectively contain (
3H) different concns of CCK-8 (ultimate density 1nM) is tested and is added thick membrane sample in the compound, so that the reaction beginning.After 90 minutes, use the glass filter suction strainer 25 ℃ of cultivations, with the washing of refrigerative 50mM Tris damping fluid.After adding Aquazol-2 cocktail, measure radioactivity.In kind carry out, replace by test compound determination contrast total binding number, and measure the non-specific binding number with Ceruletide (ultimate density 1 μ M) with 50%DMSO.
IC
50Calculating:
Calculate the ratio (%) that is combined number (total binding number (dpm)-non-specific binding number (dpm)) by the specificity of test compound in conjunction with number (total binding number (dpm)-non-specific binding number (dpm)) with the specificity of control group, draw semilogarithmic plot, the concentration corresponding to 50% is IC
50
The results are shown in the following table 1.
Table 1
Acceptor (IC
50, nM) the antiacid secretion compound number of rat tert-Amyloxycarbonyltetragastrin CCK-B CCK-A ED
50,i.d. (mg/kg) 8i 2 3 1700 8h 4 64 5000 0.014 9l 7 56 1350 0.04 8j 3 8 2200 9m 2 11 1350 7f 1 8 1650 7y 42 190 1800 7z 6 66 1900 8ha 2 42 3400 0.003 8hb 3 54 3400 0.007 15b 5 6 1150 0.026 15d 3 6 2000 16a 25 215 4400 16b 6.0 210＞10000 YM-022 2 2 100 0.107
Above result shows that The compounds of this invention has tert-Amyloxycarbonyltetragastrin/CCK-B receptor antagonism.
Following formulation example is the example of the explanation present composition.
Formulation example 1
Contain the 50mg active material, have the hard gelatine capsule agent of following composition with usual method preparation: 2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N '-(-(2-(trityl) tetrazolium-5-yl) phenyl) urea groups methyl carbon acylamino) benzophenone 7f---50mg cellulose---18mg lactose---55mg cataloid---1mg sodium carboxymethyl starch---10mg talcum powder---10mg dolomol---1mg
Formulation example 2
Contain the 50mg active material, have the hard gelatine capsule agent of following composition with usual method preparation: 2-((uncle's fourth oxygen phosphinylidyne methyl)-[3-(carboxyl phenyl) urea groups methyl phosphinylidyne]] aminoben-zophenone sodium salt 8ha---50mg cellulose---18mg lactose---55mg cataloid---1mg sodium carboxymethyl starch---10mg talcum powder---10mg dolomol---1mg
Formulation example 3
Prepare the lozenge that contains the 50mg active substance, has following composition with usual method:
2-((uncle's fourth oxygen phosphinylidyne methyl)-(3-
(carboxyl phenyl) urea groups methyl phosphinylidyne]]
Uvinul A Plus 8h---50mg
Lactose---104mg
Mierocrystalline cellulose---40mg
Polyvinylpyrrolidone---10mg
Sodium starch glycolate---22mg
Talcum powder---10mg
Magnesium Stearate---2mg
Colloid silica---2mg
Hydroxylated cellulose, glycerine and titanium dioxide
Mixture (72: 3.5: 24.5)---make the weight of 1 dressing finished product lozenge
Reach the required weight of 245mg
Formulation example 4
Contain the 50mg active material with the usual method preparation, lozenge with following composition: 2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N '-(bromophenyl) urea groups methyl carbon acylamino) benzophenone 7v---50mg lactose---104mg cellulose---40mg polyvinylpyrrolidone---10mg sodium carboxymethyl starch---22mg talcum powder---10mg dolomol---2mg cataloid---2mg hydroxylated cellulose, the mixture of glycerine and titanium dioxide (72: 3.5: 24.5)---make the weight of 1 dressing finished product lozenge
Reach the required weight of 245mg
Formulation example 5
Preparation contains the 10mg active material, has the injection solution of following composition: 2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N '-(-(carboxymethoxyl) phenyl) urea groups methyl carbon acylamino)------------------24mg propane diols---1.6ml water---complements to 4ml to 0.4ml NaOH to 80mg ethanol (95%) to the 0.06ml Sodium Benzoate to 80mg benzylalcohol to the 10mg benzoic acid to benzophenone 8j
Formulation example 6
Preparation contains the 10mg active material, has the aqueous solution for injection of following composition: 2-(N-(uncle's fourth oxygen phosphinylidyne methyl)-N '-(p-methylphenyl) urea groups methyl carbon acylamino) benzophenone 7z---10mg benzoic acid---10mg benzylalcohol---0.06ml Sodium Benzoate---10mg ethanol (95%)---0.4ml NaOH---5mg propane diols---1.6ml
Claims (9)
1. the compound shown in the general formula (I) or its pharmaceutically acceptable salt:
R in the formula
1Be hydrogen or low alkyl group; R
2Be lower alkoxy, lower alkyl amino, low-grade cycloalkyl, the optional phenyl that replaces arranged or the optional heterocycle that replaces is arranged; R
3Be that the optional phenyl that replaces is arranged; R
4Be the optional phenyl that replaces to be arranged, the optional cycloalkyl that replaces is arranged, the optional alkyl that replaces is arranged or the optional heterocycle that replaces is arranged.
2. the described compound of claim 1, wherein R
1Be hydrogen, R
2Be lower alkoxy or lower alkyl amino.
3. claim 1 or 2 described compound, wherein R
4Be that the optional phenyl that replaces is arranged.
4. the described compound of claim 3, wherein R
1Be hydrogen, R
2Be-O-tBu R
3Be carboxyl phenyl, R
4It is phenyl.
5. the described compound of claim 1, this compound is uncle's 2-[(fourth oxygen phosphinylidyne methyl)-[3-(carboxyl phenyl) urea groups methyl phosphinylidyne]] Uvinul A Plus.
6. the medical composition that contains any one described compound in the claim 1～5.
7. the described medical composition of claim 6 that gastrin receptor or CCK-B acceptor is had the specificity antagonistic action.
8. the described medical composition of claim 6 that has antiulcer action.
9. the described medical composition of claim 6 that has the effect that the drug-induced analgesic activity of class opium is strengthened or continue.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1518994 | 1994-02-09 | ||
| JP15189/94 | 1994-02-09 | ||
| JP24155594 | 1994-10-05 | ||
| JP241555/94 | 1994-10-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1145074A true CN1145074A (en) | 1997-03-12 |
Family
ID=26351304
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95192442A Pending CN1145074A (en) | 1994-02-09 | 1995-02-07 | Carbamoylmethylurea derivative |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US5739162A (en) |
| EP (1) | EP0739903B1 (en) |
| CN (1) | CN1145074A (en) |
| AT (1) | ATE212356T1 (en) |
| AU (1) | AU691565B2 (en) |
| BR (1) | BR9506763A (en) |
| CA (1) | CA2181986A1 (en) |
| DE (1) | DE69525145T2 (en) |
| ES (1) | ES2171531T3 (en) |
| FI (1) | FI963122A0 (en) |
| HU (1) | HU219913B (en) |
| MX (1) | MX9603171A (en) |
| NO (1) | NO963307L (en) |
| PT (1) | PT739903E (en) |
| RU (1) | RU2134684C1 (en) |
| TW (1) | TW294653B (en) |
| WO (1) | WO1995021856A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5804560A (en) * | 1995-01-06 | 1998-09-08 | Sibia Neurosciences, Inc. | Peptide and peptide analog protease inhibitors |
| DE69615570T2 (en) * | 1995-08-07 | 2002-07-11 | Shionogi & Co | METHOD FOR PRODUCING CARBAMOYL METHYL URINE DERIVATIVES |
| CN105377814B (en) * | 2013-07-16 | 2018-04-03 | 阿勒根公司 | The derivative for the amino acid that N ureas as formyl peptide receptor conditioning agent substitute |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0166355A2 (en) * | 1984-06-26 | 1986-01-02 | Merck & Co. Inc. | Substituted aminophenyl compounds and acylaminophenyl compounds and pharmaceutical compositions containing them |
| AU639081B2 (en) * | 1990-02-09 | 1993-07-15 | Rhone-Poulenc Rorer S.A. | N-phenyl n-acetamido glycinamides, preparation method and drugs containing them |
| FR2659334B1 (en) * | 1990-03-07 | 1992-05-15 | Rhone Poulenc Sante | N-PHENYL GLYCINAMIDE DERIVATIVES, THEIR PREPARATION AND THE MEDICINAL PRODUCTS CONTAINING THEM. |
| FR2667864B2 (en) * | 1990-03-07 | 1994-08-05 | Rhone Poulenc Sante | N-PHENYL GLYCINAMIDE DERIVATIVES, THEIR PREPARATION AND THE MEDICINAL PRODUCTS CONTAINING THEM. |
| FR2659653B1 (en) * | 1990-03-13 | 1992-05-22 | Rhone Poulenc Sante | DERIVATIVES OF UREA, THEIR PREPARATION AND THE MEDICINAL PRODUCTS CONTAINING THEM. |
-
1995
- 1995-02-07 MX MX9603171A patent/MX9603171A/en unknown
- 1995-02-07 WO PCT/JP1995/000161 patent/WO1995021856A1/en active IP Right Grant
- 1995-02-07 PT PT95907849T patent/PT739903E/en unknown
- 1995-02-07 CN CN95192442A patent/CN1145074A/en active Pending
- 1995-02-07 BR BR9506763A patent/BR9506763A/en not_active IP Right Cessation
- 1995-02-07 RU RU96119576A patent/RU2134684C1/en active
- 1995-02-07 DE DE69525145T patent/DE69525145T2/en not_active Expired - Fee Related
- 1995-02-07 EP EP95907849A patent/EP0739903B1/en not_active Expired - Lifetime
- 1995-02-07 CA CA002181986A patent/CA2181986A1/en not_active Abandoned
- 1995-02-07 ES ES95907849T patent/ES2171531T3/en not_active Expired - Lifetime
- 1995-02-07 AU AU15905/95A patent/AU691565B2/en not_active Ceased
- 1995-02-07 AT AT95907849T patent/ATE212356T1/en not_active IP Right Cessation
- 1995-02-07 HU HU9602187A patent/HU219913B/en not_active IP Right Cessation
- 1995-02-07 US US08/687,433 patent/US5739162A/en not_active Expired - Fee Related
- 1995-02-08 TW TW084101068A patent/TW294653B/zh active
-
1996
- 1996-08-08 NO NO963307A patent/NO963307L/en not_active Application Discontinuation
- 1996-08-09 FI FI963122A patent/FI963122A0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FI963122A (en) | 1996-08-09 |
| ATE212356T1 (en) | 2002-02-15 |
| AU691565B2 (en) | 1998-05-21 |
| DE69525145T2 (en) | 2002-08-29 |
| HU9602187D0 (en) | 1996-10-28 |
| PT739903E (en) | 2002-05-31 |
| WO1995021856A1 (en) | 1995-08-17 |
| EP0739903B1 (en) | 2002-01-23 |
| DE69525145D1 (en) | 2002-03-14 |
| EP0739903A1 (en) | 1996-10-30 |
| ES2171531T3 (en) | 2002-09-16 |
| FI963122A0 (en) | 1996-08-09 |
| EP0739903A4 (en) | 1998-07-08 |
| US5739162A (en) | 1998-04-14 |
| HU219913B (en) | 2001-09-28 |
| RU2134684C1 (en) | 1999-08-20 |
| NO963307L (en) | 1996-10-09 |
| HUT74950A (en) | 1997-03-28 |
| BR9506763A (en) | 1997-10-07 |
| CA2181986A1 (en) | 1995-08-17 |
| NO963307D0 (en) | 1996-08-08 |
| AU1590595A (en) | 1995-08-29 |
| MX9603171A (en) | 1997-03-29 |
| TW294653B (en) | 1997-01-01 |
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| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |